rs61733348
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The ENST00000399770.3(GRXCR1):c.777C>T(p.Ser259=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,613,982 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.014 ( 51 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 43 hom. )
Consequence
GRXCR1
ENST00000399770.3 synonymous
ENST00000399770.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.415
Genes affected
GRXCR1 (HGNC:31673): (glutaredoxin and cysteine rich domain containing 1) This gene is one of 60 loci associated with autosomal-recessive nonsyndromic hearing impairment. This gene encodes a protein which contains GRX-like domains; these domains play a role in the S-glutathionylation of proteins and may be involved in actin organization in hair cells. [provided by RefSeq, Sep 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
Variant 4-43030444-C-T is Benign according to our data. Variant chr4-43030444-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.415 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2171/152166) while in subpopulation AFR AF= 0.049 (2034/41470). AF 95% confidence interval is 0.0473. There are 51 homozygotes in gnomad4. There are 1041 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 51 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GRXCR1 | NM_001080476.3 | c.777C>T | p.Ser259= | synonymous_variant | 4/4 | ENST00000399770.3 | NP_001073945.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GRXCR1 | ENST00000399770.3 | c.777C>T | p.Ser259= | synonymous_variant | 4/4 | 1 | NM_001080476.3 | ENSP00000382670 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0143 AC: 2170AN: 152048Hom.: 51 Cov.: 32
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GnomAD3 exomes AF: 0.00364 AC: 908AN: 249480Hom.: 25 AF XY: 0.00277 AC XY: 375AN XY: 135348
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GnomAD4 exome AF: 0.00145 AC: 2120AN: 1461816Hom.: 43 Cov.: 31 AF XY: 0.00125 AC XY: 911AN XY: 727218
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GnomAD4 genome AF: 0.0143 AC: 2171AN: 152166Hom.: 51 Cov.: 32 AF XY: 0.0140 AC XY: 1041AN XY: 74402
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 09, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 23, 2018 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | Ser259Ser in Exon 04 of GRXCR1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 4.4% (142/3232) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs61733348). - |
Autosomal recessive nonsyndromic hearing loss 25 Benign:1
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at