NM_024915.4:c.1081G>A

Variant names:

• chr8-101599134-G-A
• rs770962467
• NM_024915.4:c.1081G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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:3
• Conservation: PhyloP100: 5.70
• Publications: 1 publications found

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]

GRHL2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 28

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• posterior polymorphous corneal dystrophy

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital fibrosis of extraocular muscles

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024915.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	NM_024915.4	MANE Select	c.1081G>A	p.Val361Met	missense	Exon 8 of 16	NP_079191.2
	GRHL2	NM_001330593.2		c.1033G>A	p.Val345Met	missense	Exon 8 of 16	NP_001317522.1
	GRHL2	NM_001440448.1		c.1033G>A	p.Val345Met	missense	Exon 8 of 16	NP_001427377.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	ENST00000646743.1	MANE Select	c.1081G>A	p.Val361Met	missense	Exon 8 of 16	ENSP00000495564.1
	GRHL2	ENST00000395927.1	TSL:2	c.1033G>A	p.Val345Met	missense	Exon 8 of 16	ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251314 AF XY: 0.00000736

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 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

African (AFR) AF: 0.0000300 AC: 1 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000542 AC: 6 AN: 1107830

Other (OTH) AF: 0.00 AC: 0 AN: 60230

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant nonsyndromic hearing loss 28 (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.54		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
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

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