11-71444115-C-T

Position:

• chr11-71444115-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001360.3(DHCR7):​c.199G>A​(p.Ala67Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,612,152 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:2 O:1
• Conservation: PhyloP100: 2.94

Genes affected

DHCR7 (HGNC:2860): (7-dehydrocholesterol reductase) This gene encodes an enzyme that removes the C(7-8) double bond in the B ring of sterols and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. This gene is ubiquitously expressed and its transmembrane protein localizes to the endoplasmic reticulum membrane and nuclear outer membrane. Mutations in this gene cause Smith-Lemli-Opitz syndrome (SLOS); a syndrome that is metabolically characterized by reduced serum cholesterol levels and elevated serum 7-dehydrocholesterol levels and phenotypically characterized by cognitive disability, facial dysmorphism, syndactyly of second and third toes, and holoprosencephaly in severe cases to minimal physical abnormalities and near-normal intelligence in mild cases. Alternative splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, Aug 2009]

DHCR7 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07214117).
• BP6: Variant 11-71444115-C-T is Benign according to our data. Variant chr11-71444115-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93714.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9, not_provided=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.199G>A	p.Ala67Thr	missense_variant	4/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.199G>A	p.Ala67Thr	missense_variant	4/9		NP_001157289.1
DHCR7	XM_011544777.3	c.199G>A	p.Ala67Thr	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.199G>A	p.Ala67Thr	missense_variant	4/9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.-333-54G>A		intron_variant				ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 137 AN: 152110 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000727 AC: 179 AN: 246308 Hom.: 0 AF XY: 0.000690 AC XY: 92 AN XY: 133252

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000275

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00114 AC: 1664 AN: 1459924 Hom.: 2 Cov.: 53 AF XY: 0.00109 AC XY: 791 AN XY: 726054

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.0000753

Gnomad4 NFE exome AF: 0.00138

Gnomad4 OTH exome AF: 0.000978

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152228 Hom.: 0 Cov.: 34 AF XY: 0.000860 AC XY: 64 AN XY: 74418

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00118 Hom.: 1

Bravo AF: 0.000854

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000643 AC: 78

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Smith-Lemli-Opitz syndrome Uncertain:5 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 20, 2022	The inherited c.199G>A (p.Ala67Thr) missense variant identified in the DHCR7 gene has not been reported in individuals with SLOS in the literature, it is reported in an individual with autism (PMID: 28250423) and in a control in a study of patients with SLOS (PMID: 9653161). The variant has 0.0009007 allele frequency in the gnomAD(v3) database (137 out of 152110 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. This variant has been reported in the ClinVar database as variant of uncertain significance (5 submissions) or likely benign (1 submissions) [Variation ID:93714]. The affected residue is not well conserved. In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score = 21.5, REVEL score = 0.469). Based on the available evidence, the inherited c.199G>A (p.Ala67Thr) missense variant identified in the DHCR7 gene is reported as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 15, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 23, 2023	- -

not provided Pathogenic:1 Uncertain:2 Benign:1 Other:1

Likely pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9653161, 28250423, 11241839) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Likely Benign and reported on 11-13-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 13, 2024

Variant summary: DHCR7 c.199G>A (p.Ala67Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 1612152 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.0011 vs 0.0043), allowing no conclusion about variant significance. c.199G>A has been reported in the literature in unaffected controls and absent from a Smith-Lemli-Opitz Syndrome cohort (e.g. Witsch-Baumgartner_2001), or reported as VUS, benign, or a polymorphism in control individuals without autism (e.g. Saskin_2017, Cross_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Smith-Lemli-Opitz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 38027204, 24813812, 28250423, 11241839). ClinVar contains an entry for this variant (Variation ID: 93714). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2022

The c.199G>A (p.A67T) alteration is located in exon 4 (coding exon 2) of the DHCR7 gene. This alteration results from a G to A substitution at nucleotide position 199, causing the alanine (A) at amino acid position 67 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

DHCR7-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2024

The DHCR7 c.199G>A variant is predicted to result in the amino acid substitution p.Ala67Thr. This variant was reported in a patient with autism spectrum disorder (Table S2, Saskin et al. 2017. PubMed ID: 28250423) and in a patient with tubulointerstitial disease in conjunction with a second pathogenic variant, unknown phase (Table S7, Groopman et al. 2018. PubMed ID: 30586318). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations, with recent classifications split between likely benign and uncertain significance. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;T;.;T;T;T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	.;D;T;D;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.072	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.7	L;L;.;.;.;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.68	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0090	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.024	D;D;.;.;D;.;.;D
Polyphen		0.61	P;P;.;.;.;.;.;.
Vest4		0.22
MVP		0.91
MPC		0.19
ClinPred		0.035	T
GERP RS		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143999854; hg19: chr11-71155161;