11-71435149-G-A

Position:

chr11-71435149-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001425111.1(DHCR7):c.1403C>T(p.Thr468Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00805 in 691,308 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/13 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 0.0065 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 31 hom. )

Consequence

DHCR7
NM_001425111.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.0650

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003817439).

BP6

Variant 11-71435149-G-A is Benign according to our data. Variant chr11-71435149-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 881160.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3 link	c.*226C>T		3_prime_UTR_variant	9/9	ENST00000355527.8	NP_001351.2	Q9UBM7A0A024R5F7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527 link	c.*226C>T		3_prime_UTR_variant	9/9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320 link	c.*226C>T		3_prime_UTR_variant	8/8			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.00655

AC:

997

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.0329

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00843

AC:

1105

AN:

131060

Hom.:

AF XY:

0.00837

AC XY:

599

AN XY:

71554

show subpopulations

Gnomad AFR exome

AF:

0.00195

Gnomad AMR exome

AF:

0.00369

Gnomad ASJ exome

AF:

0.0376

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00357

Gnomad FIN exome

AF:

0.00314

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00893

GnomAD4 exome

AF:

0.00848

AC:

4569

AN:

539020

Hom.:

Cov.:

AF XY:

0.00835

AC XY:

2439

AN XY:

291970

show subpopulations

Gnomad4 AFR exome

AF:

0.00173

Gnomad4 AMR exome

AF:

0.00368

Gnomad4 ASJ exome

AF:

0.0368

Gnomad4 EAS exome

AF:

0.0000321

Gnomad4 SAS exome

AF:

0.00344

Gnomad4 FIN exome

AF:

0.00462

Gnomad4 NFE exome

AF:

0.00976

Gnomad4 OTH exome

AF:

0.00904

GnomAD4 genome

AF:

0.00655

AC:

997

AN:

152288

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

427

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00173

Gnomad4 AMR

AF:

0.00470

Gnomad4 ASJ

AF:

0.0329

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.0101

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.00658

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0132

AC:

ExAC

AF:

0.00280

AC:

189

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	DHCR7: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Smith-Lemli-Opitz syndrome

Uncertain:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

3.0

DANN

Benign

0.43

DEOGEN2

Benign

0.22

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0038

MetaSVM

Uncertain

0.42

PROVEAN

Benign

1.1

REVEL

Benign

0.18

Sift

Pathogenic

0.0

MVP

0.20

ClinPred

0.0050

GERP RS

-4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over