rs770962467

Positions:

• chr8-101599134-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_024915.4(GRHL2):​c.1081G>A​(p.Val361Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000549 in 1,457,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.70

Genes affected

GRHL2 (HGNC:2799): (grainyhead like transcription factor 2) The protein encoded by this gene is a transcription factor that can act as a homodimer or as a heterodimer with either GRHL1 or GRHL3. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal dominant type 28 (DFNA28).[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.1081G>A	p.Val361Met	missense_variant	8/16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.1033G>A	p.Val345Met	missense_variant	8/16		NP_001317522.1
GRHL2	XM_011517306.4	c.1033G>A	p.Val345Met	missense_variant	8/16		XP_011515608.1
GRHL2	XM_011517307.4	c.1081G>A	p.Val361Met	missense_variant	8/16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.1081G>A	p.Val361Met	missense_variant	8/16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1	c.1033G>A	p.Val345Met	missense_variant	8/16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251314 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457222 Hom.: 0 Cov.: 29 AF XY: 0.00000414 AC XY: 3 AN XY: 725310

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 28, 2017

The p.Val361Met variant in GRHL2 has not been previously reported in individuals with hearing loss, but has been identified in 3/126630 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770962467). Although this variant has been seen in the general population, it s frequency is not high enough to rule out a pathogenic role. Computational pred iction tools and conservation analysis suggest the variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val361Met variant is uncertain. A CMG/AMP Criteria applied: PM2, PP3. -

Autosomal dominant nonsyndromic hearing loss 28 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Variants causing autosomal dominant deafness and autosomal recessive ectodermal dysplasia/short stature syndrome are due to a loss of function, however variants observed in autosomal dominant corneal dystrophy result in a gain of function (OMIM). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Deafness and corneal dystrophy are both dominantly inherited, whereas ectodermal dysplasia/short stature syndrome is a recessive condition (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 8). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD (v2) <0.001 (3 heterozygotes, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (CP2 transcription factor domain; NCBI, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are inconclusive. The variant has previously been classified as a VUS (ClinVar). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N;.;N
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.013	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.46
MutPred		0.54		Gain of ubiquitination at K366 (P = 0.1162);Gain of ubiquitination at K366 (P = 0.1162);.;
MVP		0.11
MPC		1.1
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.79
gMVP		0.64

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

Other links and lift over

dbSNP: rs770962467; hg19: chr8-102611362; COSMIC: COSV52547682;