rs201466849
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The ENST00000685320.1(DHCR7):c.-186G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000608 in 1,612,810 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
ENST00000685320.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.400G>T | p.Val134Leu | missense_variant | 5/9 | ENST00000355527.8 | NP_001351.2 | |
DHCR7 | NM_001163817.2 | c.400G>T | p.Val134Leu | missense_variant | 5/9 | NP_001157289.1 | ||
DHCR7 | XM_011544777.3 | c.400G>T | p.Val134Leu | missense_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000685320.1 | c.-186G>T | 5_prime_UTR_premature_start_codon_gain_variant | 4/8 | ENSP00000509319.1 | |||||
DHCR7 | ENST00000355527.8 | c.400G>T | p.Val134Leu | missense_variant | 5/9 | 1 | NM_001360.3 | ENSP00000347717.4 | ||
DHCR7 | ENST00000685320.1 | c.-186G>T | 5_prime_UTR_variant | 4/8 | ENSP00000509319.1 |
Frequencies
GnomAD3 genomes AF: 0.000362 AC: 55AN: 152064Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000721 AC: 18AN: 249662Hom.: 0 AF XY: 0.0000519 AC XY: 7AN XY: 134900
GnomAD4 exome AF: 0.0000288 AC: 42AN: 1460628Hom.: 0 Cov.: 31 AF XY: 0.0000317 AC XY: 23AN XY: 726554
GnomAD4 genome AF: 0.000368 AC: 56AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74388
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 25, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 04, 2018 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 22, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2024 | Reported in an individual with SLOS in published literature; however, it is not known if this patient harbored a second variant in DHCR7 (PMID: 23042628); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23891399, 24813812, 29300326, 23042628) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 09, 2024 | Variant summary: DHCR7 c.400G>T (p.Val134Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249662 control chromosomes, predominantly at a frequency of 0.00081 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (7.2e-05 vs 0.0043), allowing no conclusion about variant significance. c.400G>T has been reported in the literature in unspecified individuals affected with Smith-Lemli-Opitz Syndrome, without strong evidence for causality (Waterham_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Smith-Lemli-Opitz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23042628). ClinVar contains an entry for this variant (Variation ID: 93718). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2018 | The p.V134L variant (also known as c.400G>T), located in coding exon 3 of the DHCR7 gene, results from a G to T substitution at nucleotide position 400. The valine at codon 134 is replaced by leucine, an amino acid with highly similar properties. This alteration was identified and considered causative in one study; however, no information regarding patient phenotype or second allele genotype was provided (Waterham HR et al. Am J Med Genet C Semin Med Genet, 2012 Nov;160C:263-84; Cross JL et al. Clin. Genet., 2015 Jun;87:570-5). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at