rs374891838
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_014425.5(INVS):c.2776G>A(p.Ala926Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,613,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A926A) has been classified as Likely benign.
Frequency
Consequence
NM_014425.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INVS | NM_014425.5 | c.2776G>A | p.Ala926Thr | missense_variant | 14/17 | ENST00000262457.7 | |
INVS | NM_001318381.2 | c.2488G>A | p.Ala830Thr | missense_variant | 15/18 | ||
INVS | NM_001318382.2 | c.1798G>A | p.Ala600Thr | missense_variant | 14/17 | ||
INVS | NR_134606.2 | n.2925G>A | non_coding_transcript_exon_variant | 14/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INVS | ENST00000262457.7 | c.2776G>A | p.Ala926Thr | missense_variant | 14/17 | 1 | NM_014425.5 | A2 | |
INVS | ENST00000262456.6 | c.2266G>A | p.Ala756Thr | missense_variant | 15/18 | 5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000100 AC: 25AN: 249446Hom.: 0 AF XY: 0.000104 AC XY: 14AN XY: 135204
GnomAD4 exome AF: 0.000153 AC: 223AN: 1461296Hom.: 0 Cov.: 35 AF XY: 0.000149 AC XY: 108AN XY: 726966
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74374
ClinVar
Submissions by phenotype
Infantile nephronophthisis Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 30, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2023 | The c.2776G>A (p.A926T) alteration is located in exon 14 (coding exon 13) of the INVS gene. This alteration results from a G to A substitution at nucleotide position 2776, causing the alanine (A) at amino acid position 926 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Nephronophthisis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 926 of the INVS protein (p.Ala926Thr). This variant is present in population databases (rs374891838, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with INVS-related conditions. ClinVar contains an entry for this variant (Variation ID: 194408). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 04, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at