rs199768740
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_001366722.1(GRIP1):c.160G>A(p.Val54Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000954 in 1,613,946 control chromosomes in the GnomAD database, including 5 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_001366722.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GRIP1 | NM_001366722.1 | c.160G>A | p.Val54Ile | missense_variant | Exon 3 of 25 | ENST00000359742.9 | NP_001353651.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000907 AC: 138AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00126 AC: 313AN: 249328Hom.: 0 AF XY: 0.00123 AC XY: 166AN XY: 135246
GnomAD4 exome AF: 0.000959 AC: 1402AN: 1461706Hom.: 5 Cov.: 31 AF XY: 0.00100 AC XY: 727AN XY: 727164
GnomAD4 genome AF: 0.000906 AC: 138AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.000873 AC XY: 65AN XY: 74432
ClinVar
Submissions by phenotype
Fraser syndrome 3 Uncertain:3Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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Abnormal brain morphology Pathogenic:1Uncertain:1
NM_021150.3:c.160G>A in the GRIP1 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Karaca et al. identified c.160G>A compound with c.1142G>T (phase unknown) in a neurologic patient. Two variants are novel with high frequency in Turkish Exomes (PMID: 26539891). We interpret it as a variant of uncertain significance. ACMG/AMP criteria applied: Null. -
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not specified Uncertain:1
Variant summary: GRIP1 c.160G>A (p.Val54Ile) results in a conservative amino acid change located in the PDZ domain (IPR001478) of 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 0.0013 in 249328 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GRIP1 causing Cryptophthalmos Syndrome (0.0013 vs 0.0013), allowing no conclusion about variant significance. c.160G>A has been reported in the literature in one compound heterozygous individual affected with agenesis of the corpus callosum and subependymal heterotopia (Karaca_2015). These data do not allow any conclusion about variant significance with Cryptophthalmos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: three classify the variant as of uncertain significance, one as likely benign, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at