NM_024915.4:c.34G>A

Variant names:

• chr8-101543254-G-A
• rs749906501
• NM_024915.4:c.34G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024915.4(GRHL2):​c.34G>A​(p.Val12Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V12L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.34G>A	p.Val12Met	missense_variant	Exon 2 of 16	ENST00000646743.1	NP_079191.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.34G>A	p.Val12Met	missense_variant	Exon 2 of 16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000472106.2	n.362G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
GRHL2	ENST00000395927.1	c.-15G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 16	2		ENSP00000379260.1
GRHL2	ENST00000395927.1	c.-15G>A		5_prime_UTR_variant	Exon 2 of 16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		7.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.99	N;.
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.045	D;.
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.31		Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);
MVP		0.24
MPC		1.1
ClinPred		0.92	D
GERP RS		6.0
Varity_R		0.21
gMVP		0.66
Mutation Taster		=230/70	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: rs749906501; hg19: chr8-102555482;