17-38337639-AG-A
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1PM2PP5_Very_StrongBS1_Supporting
The NM_001004334.4(GPR179):c.984delC(p.Ser329LeufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,611,632 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001004334.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GPR179 | NM_001004334.4 | c.984delC | p.Ser329LeufsTer4 | frameshift_variant | Exon 3 of 11 | ENST00000616987.5 | NP_001004334.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GPR179 | ENST00000616987.5 | c.984delC | p.Ser329LeufsTer4 | frameshift_variant | Exon 3 of 11 | 1 | NM_001004334.4 | ENSP00000483469.2 |
Frequencies
GnomAD3 genomes AF: 0.000466 AC: 71AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000508 AC: 126AN: 248208Hom.: 1 AF XY: 0.000557 AC XY: 75AN XY: 134738
GnomAD4 exome AF: 0.000337 AC: 492AN: 1459406Hom.: 1 Cov.: 31 AF XY: 0.000368 AC XY: 267AN XY: 726000
GnomAD4 genome AF: 0.000466 AC: 71AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38AN XY: 74376
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Reported previously in the homozygous state and in the compound heterozygous state with another GPR179 variant, in association with congenital stationary night blindness (Peachey et al., 2012; Audo et al., 2012; Carss et al., 2017); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30609409, 30487145, 22325361, 28041643, 31980526, 32581362, 31589614, 27535533, 22325362) -
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This sequence change creates a premature translational stop signal (p.Ser329Leufs*4) in the GPR179 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GPR179 are known to be pathogenic (PMID: 22325361, 22325362). This variant is present in population databases (rs770066665, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with congenital stationary night blindness (PMID: 22325361). ClinVar contains an entry for this variant (Variation ID: 31204). For these reasons, this variant has been classified as Pathogenic. -
Congenital stationary night blindness 1E Pathogenic:3
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive complete congenital stationary night blindness, type 1E (MIM#614565). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (150 heterozygotes, 1 homozygote). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other loss of function variants have previously been classified as pathogenic in individuals with night blindness (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as in multiple individuals with autosomal recessive complete congenital stationary night blindness (ClinVar, PMID: 22325361, PMID: 22325362). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Criteria applied: PVS1,PS4_MOD,PM2_SUP -
Retinal dystrophy Pathogenic:2
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Congenital stationary night blindness Pathogenic:2
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The p.Ser329LeufsX4 variant in GPR179 has been reported three individuals with c omplete congenital stationary night blindness in the compound heterozygous state (Audo 2012, Peachey 2012). This variant has also been identified in 61/120,604 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs770066665). This p.Ser329LeufsX4 variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at posit ion 329 and leads to a premature termination codon 4 amino acids downstream. Thi s alteration is then predicted to lead to a truncated or absent protein. In summ ary, this variant meets criteria to be classified as pathogenic for congenital s tationary night blindness in an autosomal recessive manner based upon case obser vations, low frequency in controls, and a predicted null effect on protein funct ion. -
Congenital Stationary Night Blindness, Recessive Pathogenic:1
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Optic atrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at