Genetic Variant DHCR7:p.Ala41Glu (chr11-71444192-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_001360.3(DHCR7):c.122C>A(p.Ala41Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,352 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A41V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64

Publications

0 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 4 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity DHCR7_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001360.3

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3 link	c.122C>A	p.Ala41Glu	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.122C>A	p.Ala41Glu	missense_variant	Exon 4 of 9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320.1 link	c.-333-131C>A		intron_variant	Intron 2 of 7			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445352

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717274

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33258

American (AMR)

AF:

0.00

AC:

AN:

42282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25816

East Asian (EAS)

AF:

0.00

AC:

AN:

39126

South Asian (SAS)

AF:

0.00

AC:

AN:

83886

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103384

Other (OTH)

AF:

0.00

AC:

AN:

59798

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Uncertain

0.68

D;D;T;T;T;.;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.91

.;D;D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.3

M;M;.;.;.;.;.

PhyloP100

1.6

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.1

N;N;N;N;N;D;D

REVEL

Uncertain

0.64

Sift

Benign

0.28

T;T;T;D;D;D;D

Sift4G

Benign

0.14

T;T;.;D;.;.;D

Polyphen

0.79

P;P;.;.;.;.;.

Vest4

0.56

MutPred

0.68

Loss of glycosylation at S42 (P = 0.2526);Loss of glycosylation at S42 (P = 0.2526);Loss of glycosylation at S42 (P = 0.2526);Loss of glycosylation at S42 (P = 0.2526);Loss of glycosylation at S42 (P = 0.2526);.;Loss of glycosylation at S42 (P = 0.2526);

MVP

0.89

MPC

0.38

ClinPred

0.21

GERP RS

-0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.093

gMVP

0.73

Mutation Taster

=96/4

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over