rs587777738

Positions:

• chr8-101632325-T-A
• chr8-101632325-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_024915.4(GRHL2):​c.1445T>A​(p.Ile482Lys) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.43

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 (HGNC:):

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, 0.856
• PP5: Variant 8-101632325-T-A is Pathogenic according to our data. Variant chr8-101632325-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 156217.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.1445T>A	p.Ile482Lys	missense_variant	11/16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.1397T>A	p.Ile466Lys	missense_variant	11/16		NP_001317522.1
GRHL2	XM_011517306.4	c.1397T>A	p.Ile466Lys	missense_variant	11/16		XP_011515608.1
GRHL2	XM_011517307.4	c.1445T>A	p.Ile482Lys	missense_variant	11/16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.1445T>A	p.Ile482Lys	missense_variant	11/16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1	c.1397T>A	p.Ile466Lys	missense_variant	11/16	2		ENSP00000379260.1
GRHL2	ENST00000517674.5	n.100T>A		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	30
DANN	Benign	0.97
DEOGEN2	Uncertain	0.76	D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.2	M;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.5	D;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.018	D;.;D
Polyphen		0.98	D;D;.
Vest4		0.94
MutPred		0.66		Gain of catalytic residue at I482 (P = 0.01);Gain of catalytic residue at I482 (P = 0.01);.;
MVP		0.51
MPC		1.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.86
gMVP		0.80

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: rs587777738; hg19: chr8-102644553;