rs72954276

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_001360.3(DHCR7):c.1012G>A(p.Val338Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000918 in 1,608,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.00078 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00093 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: -1.07

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

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

DHCR7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001360.3

BP4

Computational evidence support a benign effect (MetaRNN=0.01096943).

BP6

Variant 11-71435791-C-T is Benign according to our data. Variant chr11-71435791-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93706.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DHCR7	NM_001360.3	MANE Select	c.1012G>A	p.Val338Met	missense	Exon 9 of 9	NP_001351.2
DHCR7	NM_001425107.1		c.1063G>A	p.Val355Met	missense	Exon 10 of 10	NP_001412036.1
DHCR7	NM_001425108.1		c.1048G>A	p.Val350Met	missense	Exon 9 of 9	NP_001412037.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.1012G>A	p.Val338Met	missense	Exon 9 of 9	ENSP00000347717.4
DHCR7	ENST00000407721.6	TSL:1	c.1012G>A	p.Val338Met	missense	Exon 9 of 9	ENSP00000384739.2
DHCR7	ENST00000685320.1		c.427G>A	p.Val143Met	missense	Exon 8 of 8	ENSP00000509319.1

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000913

AC:

224

AN:

245410

AF XY:

0.000882

show subpopulations

Gnomad AFR exome

AF:

0.000448

Gnomad AMR exome

AF:

0.000785

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00314

Gnomad FIN exome

AF:

0.0000954

Gnomad NFE exome

AF:

0.00112

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000933

AC:

1358

AN:

1455750

Hom.:

Cov.:

AF XY:

0.000937

AC XY:

678

AN XY:

723226

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

33392

American (AMR)

AF:

0.000896

AC:

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00144

AC:

AN:

39558

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86136

European-Finnish (FIN)

AF:

0.000270

AC:

AN:

51908

Middle Eastern (MID)

AF:

0.000696

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00106

AC:

1171

AN:

1108230

Other (OTH)

AF:

0.00103

AC:

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

169

254

338

423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000781

AC:

119

AN:

152352

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41590

American (AMR)

AF:

0.00124

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00290

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

68028

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.000873

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000932

AC:

ExAC

AF:

0.000825

AC:

100

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Smith-Lemli-Opitz syndrome (4)

not provided (2)

DHCR7-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

0.098

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.78

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.66

M_CAP

Benign

0.060

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.9

PhyloP100

-1.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.33

REVEL

Benign

0.26

Sift

Benign

0.28

Sift4G

Benign

0.27

Polyphen

0.025

Vest4

0.066

MVP

0.68

MPC

0.15

ClinPred

0.0029

GERP RS

-7.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.025

gMVP

0.64

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over