chr8-101632325-T-A

Variant names:

• chr8-101632325-T-A
• rs587777738
• NM_024915.4:c.1445T>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 3 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):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 28

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), 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 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 VariationId is 156217.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	NM_024915.4	MANE Select	c.1445T>A	p.Ile482Lys	missense	Exon 11 of 16	NP_079191.2	Q6ISB3-1
	GRHL2	NM_001330593.2		c.1397T>A	p.Ile466Lys	missense	Exon 11 of 16	NP_001317522.1	Q6ISB3-2
	GRHL2	NM_001440448.1		c.1397T>A	p.Ile466Lys	missense	Exon 11 of 16	NP_001427377.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	ENST00000646743.1	MANE Select	c.1445T>A	p.Ile482Lys	missense	Exon 11 of 16	ENSP00000495564.1	Q6ISB3-1
	GRHL2	ENST00000395927.1	TSL:2	c.1397T>A	p.Ile466Lys	missense	Exon 11 of 16	ENSP00000379260.1	Q6ISB3-2
	GRHL2	ENST00000907653.1		c.1232T>A	p.Ile411Lys	missense	Exon 9 of 14	ENSP00000577712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.018	D
Polyphen		0.98	D
Vest4		0.94
MutPred		0.66		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
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs587777738; hg19: chr8-102644553;