dbSNP rs143999854: DHCR7:p.Ala67Ser (chr11-71444115-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001360.3(DHCR7):c.199G>T(p.Ala67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A67T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.94

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_001360.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1325019).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3 link	c.199G>T	p.Ala67Ser	missense_variant	Exon 4 of 9	ENST00000355527.8	NP_001351.2	Q9UBM7A0A024R5F7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8 link	c.199G>T	p.Ala67Ser	missense_variant	Exon 4 of 9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320.1 link	c.-333-54G>T		intron_variant	Intron 2 of 7			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000812

AC:

AN:

246308

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726056

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.00

AC:

AN:

85832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111276

Other (OTH)

AF:

0.00

AC:

AN:

60326

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

4.8

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.31

T;T;.;T;T;T;.;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.77

.;T;T;T;T;T;T;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.13

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

-1.6

N;N;.;.;.;.;.;.

PhyloP100

2.9

PrimateAI

Benign

0.32

PROVEAN

Benign

1.6

N;N;N;N;N;N;N;N

REVEL

Uncertain

0.31

Sift

Benign

1.0

T;T;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;.;.;T;.;.;T

Polyphen

0.0010

B;B;.;.;.;.;.;.

Vest4

0.093

MutPred

0.62

Gain of glycosylation at A67 (P = 0.0391);Gain of glycosylation at A67 (P = 0.0391);.;Gain of glycosylation at A67 (P = 0.0391);Gain of glycosylation at A67 (P = 0.0391);Gain of glycosylation at A67 (P = 0.0391);.;Gain of glycosylation at A67 (P = 0.0391);

MVP

0.78

MPC

0.11

ClinPred

0.026

GERP RS

0.28

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.37

Mutation Taster

=94/6

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over