11-71441420-T-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001360.3(DHCR7):c.433A>C(p.Ile145Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I145T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001360.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.433A>C | p.Ile145Leu | missense_variant | Exon 6 of 9 | ENST00000355527.8 | NP_001351.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461172Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726848
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:3Uncertain:1
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The c.433A>C;p.(Ile145Leu) missense change has been observed in affected individual(s) (PMID: 20556518; 15954111; 30925529) - PS4. This variant is not present in population databases:rs1555146475, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Ile145Leu) was detected in trans with a Pathogenic variant (PMID: 20556518; 15954111; 30925529) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 30925529) - PP1. In summary, the currently available evidence indicates that the variant is Pathogenic -
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DHCR7 protein function. ClinVar contains an entry for this variant (Variation ID: 558625). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 15954111, 20556518). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 145 of the DHCR7 protein (p.Ile145Leu). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at