chr1-24331548-T-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PVS1_SupportingBS2
The NM_001195010.2(GRHL3):āc.2T>Cā(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000821 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_001195010.2 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251418Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135886
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461850Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727230
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.Met47Thr (NM_198174.2: c.140T>C) variant in GRHL3 has not been previously reported in affected individuals, but has been identified in 0.02% (4/18394) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computation al prediction tools and conservation analysis do not provide strong support for or against an impact of the p.Met47Thr change to the protein. It should be noted that the methionine (Met) residue impacted by this variant represents the trans lation start site of an alternative GRHL3 transcript (NM_001195010.1:c.2T>C, p.M et1?). However, the NM_001195010.1 transcript is poorly expressed (see ENST00000 356046.6 in GTEx; https://gtexportal.org/) and a second Met is present at the ne ighboring residue (p.Met2). As a result, the predicted start site impact is less likely to have biological significance. In summary, the clinical significance o f the p.Met47Thr variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting . -
GRHL3-related disorder Uncertain:1
The GRHL3 c.2T>C variant is predicted to disrupt the translation initiation site (Start Loss). In the canonical transcript NM_198174 is this variant annotated as p.Met47Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Inborn genetic diseases Uncertain:1
The c.140T>C (p.M47T) alteration is located in exon 2 (coding exon 2) of the GRHL3 gene. This alteration results from a T to C substitution at nucleotide position 140, causing the methionine (M) at amino acid position 47 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at