Genetic Variant DHCR7:c.-265G>A (chr11-71443993-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001360.3(DHCR7):c.321G>A(p.Gln107Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000686 in 1,458,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 splice_region, synonymous

Scores

Splicing: ADA: 0.9999

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.57

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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women's Health

DHCR7 links:

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new If you want to explore the variant's impact on the transcript NM_001360.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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	UniProt
DHCR7	NM_001360.3	MANE Select	c.321G>A	p.Gln107Gln	splice_region synonymous	Exon 4 of 9	NP_001351.2	A0A024R5F7
DHCR7	NM_001425107.1		c.321G>A	p.Gln107Gln	splice_region synonymous	Exon 4 of 10	NP_001412036.1	A0A804HI25
DHCR7	NM_001425108.1		c.321G>A	p.Gln107Gln	synonymous	Exon 4 of 9	NP_001412037.1	A0A804HJQ7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DHCR7	ENST00000685320.1		c.-265G>A		splice_region	Exon 3 of 8	ENSP00000509319.1	B4E1K5
DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.321G>A	p.Gln107Gln	splice_region synonymous	Exon 4 of 9	ENSP00000347717.4	Q9UBM7
DHCR7	ENST00000407721.6	TSL:1	c.321G>A	p.Gln107Gln	splice_region synonymous	Exon 4 of 9	ENSP00000384739.2	Q9UBM7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25914

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110130

Other (OTH)

AF:

0.00

AC:

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Benign

0.85

PhyloP100

6.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.86

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.75

Position offset: -36

DS_DL_spliceai

0.86

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over