8-101619632-T-C

Position:

• chr8-101619632-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_024915.4(GRHL2):​c.1192T>C​(p.Tyr398His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.02

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818
• PP5: Variant 8-101619632-T-C is Pathogenic according to our data. Variant chr8-101619632-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 156216.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.1192T>C	p.Tyr398His	missense_variant	9/16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.1144T>C	p.Tyr382His	missense_variant	9/16		NP_001317522.1
GRHL2	XM_011517306.4	c.1144T>C	p.Tyr382His	missense_variant	9/16		XP_011515608.1
GRHL2	XM_011517307.4	c.1192T>C	p.Tyr398His	missense_variant	9/16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.1192T>C	p.Tyr398His	missense_variant	9/16		NM_024915.4	ENSP00000495564	P1
GRHL2	ENST00000395927.1	c.1144T>C	p.Tyr382His	missense_variant	9/16	2		ENSP00000379260

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratoire de Génétique Moléculaire, CHU Bordeaux

-

- -

Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	D;.;D
REVEL	Pathogenic	0.74
Sift	Benign	0.23	T;.;D
Sift4G	Benign	0.53	T;.;T
Polyphen		0.99	D;D;.
Vest4		0.88
MutPred		0.66		Gain of disorder (P = 0.0361);Gain of disorder (P = 0.0361);.;
MVP		0.093
MPC		1.3
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.72
gMVP		0.48

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: rs587777737; hg19: chr8-102631860;