Variant chr1-24331548-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PVS1_SupportingBS2

The NM_001195010.2(GRHL3):c.2T>C(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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

GRHL3
NM_001195010.2 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.17

Variant links:

Genes affected

GRHL3 (HGNC:25839): (grainyhead like transcription factor 3) This gene encodes a member of the grainyhead family of transcription factors. The encoded protein may function as a transcription factor during development, and has been shown to stimulate migration of endothelial cells. Multiple transcript variants encoding distinct isoforms have been identified for this gene.[provided by RefSeq, Aug 2010]

GRHL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 3 CDS bases. Genomic position: 24331549. Lost 0.002 part of the original CDS.

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL3	NM_198173.3 link	c.140T>C	p.Met47Thr	missense_variant	Exon 2 of 16	ENST00000361548.9	NP_937816.1	Q8TE85-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL3	ENST00000361548.9 link	c.140T>C	p.Met47Thr	missense_variant	Exon 2 of 16	1	NM_198173.3	ENSP00000354943.5		Q8TE85-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251418

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 20, 2018

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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

.;D;.;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D;D

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.50

D;D;D;D;D

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.6

M;M;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.9

D;D;D;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

0.28

.;.;.;.;B

Vest4

0.83

MutPred

0.46

Gain of ubiquitination at K45 (P = 0.0689);Gain of ubiquitination at K45 (P = 0.0689);.;.;.;

MVP

0.33

MPC

0.68

ClinPred

0.48

GERP RS

5.9

Varity_R

0.69

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over