NM_001360.3:c.376G>A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001360.3(DHCR7):c.376G>A(p.Val126Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000116 in 1,613,814 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001360.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.376G>A | p.Val126Ile | missense_variant | Exon 5 of 9 | ENST00000355527.8 | NP_001351.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152060Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000120 AC: 30AN: 250706Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135498
GnomAD4 exome AF: 0.000101 AC: 147AN: 1461636Hom.: 2 Cov.: 31 AF XY: 0.0000963 AC XY: 70AN XY: 727082
GnomAD4 genome AF: 0.000269 AC: 41AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74406
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Uncertain:6Benign:1
ACMG classification criteria: PM2 moderate -
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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not provided Uncertain:3
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Variant identified in a patient with autism; however, it is unclear whether a second variant in this gene was identified (PMID: 28250423); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in homozygous state in an adult with normal serum cholesterol and no reported features of SLOS (PMID: 34168679); This variant is associated with the following publications: (PMID: 31130284, 28250423, 24813812, 29300326, 34168679) -
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not specified Uncertain:1
Variant summary: DHCR7 c.376G>A (p.Val126Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250706 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.00012 vs 0.0043), allowing no conclusion about variant significance. c.376G>A has been reported in the literature in a homozygous 12 months old dysmorphic male with microcephaly, and strabismus (example: Monies_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34168679, 24813812, 31130284, 28250423). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Inborn genetic diseases Uncertain:1
The c.376G>A (p.V126I) alteration is located in exon 5 (coding exon 3) of the DHCR7 gene. This alteration results from a G to A substitution at nucleotide position 376, causing the valine (V) at amino acid position 126 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
DHCR7-related disorder Uncertain:1
The DHCR7 c.376G>A variant is predicted to result in the amino acid substitution p.Val126Ile. This variant was reported in individuals with Smith-Lemli-Opitz syndrome (Cross et al. 2015. PubMed ID: 24813812; Saskin et al. 2017. PubMed ID: 28250423; Monies et al. 2019. PubMed ID: 31130284; Alharazy et al. 2021. PubMed ID: 34168679). This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at