rs760241

Variant names:

• chr11-71435645-A-G
• rs760241
• NM_001360.3:c.1158T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-71435645-A-G
• chr11-71435645-A-C
• chr11-71435645-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001425112.1(DHCR7):​c.1292T>C​(p.Met431Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,612,582 control chromosomes in the GnomAD database, including 679,833 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M431I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.85 (56400 hom., cov: 36)
  • Exomes 𝑓: 0.92 (623433 hom.)
• Consequence: DHCR7 NM_001425112.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.535
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• Smith-Lemli-Opitz syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, ClinGen, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.5435136E-7).
• BP6: Variant 11-71435645-A-G is Benign according to our data. Variant chr11-71435645-A-G is described in ClinVar as Benign. ClinVar VariationId is 93707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425112.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	NM_001360.3	MANE Select	c.1158T>C	p.Asp386Asp	synonymous	Exon 9 of 9	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425112.1		c.1292T>C	p.Met431Thr	missense	Exon 9 of 9	NP_001412041.1
	DHCR7	NM_001425116.1		c.1196T>C	p.Met399Thr	missense	Exon 9 of 9	NP_001412045.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.1158T>C	p.Asp386Asp	synonymous	Exon 9 of 9	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.1158T>C	p.Asp386Asp	synonymous	Exon 9 of 9	ENSP00000384739.2	Q9UBM7
	DHCR7	ENST00000685320.1		c.573T>C	p.Asp191Asp	synonymous	Exon 8 of 8	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes AF: 0.853 AC: 129845 AN: 152178 Hom.: 56403 Cov.: 36

Gnomad AFR AF: 0.708

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.945

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.955

Gnomad OTH AF: 0.862

GnomAD2 exomes AF: 0.852 AC: 210542 AN: 247048 AF XY: 0.854

Gnomad AFR exome AF: 0.704

Gnomad AMR exome AF: 0.740

Gnomad ASJ exome AF: 0.844

Gnomad EAS exome AF: 0.786

Gnomad FIN exome AF: 0.946

Gnomad NFE exome AF: 0.949

Gnomad OTH exome AF: 0.879

GnomAD4 exome AF: 0.920 AC: 1342808 AN: 1460286 Hom.: 623433 Cov.: 85 AF XY: 0.914 AC XY: 663922 AN XY: 726546

African (AFR) AF: 0.696 AC: 23293 AN: 33476

American (AMR) AF: 0.748 AC: 33438 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 22048 AN: 26120

East Asian (EAS) AF: 0.798 AC: 31689 AN: 39686

South Asian (SAS) AF: 0.686 AC: 59186 AN: 86254

European-Finnish (FIN) AF: 0.945 AC: 49162 AN: 52008

Middle Eastern (MID) AF: 0.791 AC: 4560 AN: 5768

European-Non Finnish (NFE) AF: 0.959 AC: 1066034 AN: 1111914

Other (OTH) AF: 0.884 AC: 53398 AN: 60372

GnomAD4 genome AF: 0.853 AC: 129865 AN: 152296 Hom.: 56400 Cov.: 36 AF XY: 0.849 AC XY: 63218 AN XY: 74476

African (AFR) AF: 0.707 AC: 29378 AN: 41558

American (AMR) AF: 0.806 AC: 12338 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2889 AN: 3468

East Asian (EAS) AF: 0.781 AC: 4039 AN: 5170

South Asian (SAS) AF: 0.675 AC: 3258 AN: 4826

European-Finnish (FIN) AF: 0.945 AC: 10051 AN: 10632

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.955 AC: 64938 AN: 68010

Other (OTH) AF: 0.860 AC: 1820 AN: 2116

Alfa AF: 0.905 Hom.: 57718

Bravo AF: 0.837

TwinsUK AF: 0.962 AC: 3568

ALSPAC AF: 0.959 AC: 3696

ESP6500AA AF: 0.725 AC: 3191

ESP6500EA AF: 0.946 AC: 8124

ExAC AF: 0.853 AC: 103424

Asia WGS AF: 0.650 AC: 2263 AN: 3478

EpiCase AF: 0.949

EpiControl AF: 0.948

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	5	Smith-Lemli-Opitz syndrome (5)
-	-	2	not provided (2)
-	-	1	DHCR7-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	0.069
DANN	Benign	0.13
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-0.88	T
PhyloP100		-0.54
PROVEAN	Benign	0.43	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
ClinPred		0.022	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs760241; hg19: chr11-71146691; COSMIC: COSV62795292; COSMIC: COSV62795292;