rs727504883

Variant names:

• chr8-101558583-T-G
• rs727504883
• NM_024915.4:c.449T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024915.4(GRHL2):​c.449T>G​(p.Ile150Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13626263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.449T>G	p.Ile150Ser	missense_variant	Exon 4 of 16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.401T>G	p.Ile134Ser	missense_variant	Exon 4 of 16		NP_001317522.1
GRHL2	NM_001440448.1	c.401T>G	p.Ile134Ser	missense_variant	Exon 4 of 16		NP_001427377.1
GRHL2	NM_001440447.1	c.449T>G	p.Ile150Ser	missense_variant	Exon 4 of 16		NP_001427376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.449T>G	p.Ile150Ser	missense_variant	Exon 4 of 16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1	c.401T>G	p.Ile134Ser	missense_variant	Exon 4 of 16	2		ENSP00000379260.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ile150Ser variant in GRHL2 has not been previously reported in individuals w ith hearing loss or in large population studies. Computational analyses (biochem ical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, add itional information is needed to determine the clinical significance of this var iant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.053	T;T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.79	.;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.
PhyloP100		3.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.39	N;.;N
REVEL	Benign	0.10
Sift	Benign	0.24	T;.;T
Sift4G	Benign	0.31	T;.;T
Polyphen		0.0010	B;B;.
Vest4		0.52
MutPred		0.51		Gain of disorder (P = 0.0019);Gain of disorder (P = 0.0019);.;
MVP		0.043
MPC		0.53
ClinPred		0.31	T
GERP RS		4.6
Varity_R		0.10
gMVP		0.38
Mutation Taster		=82/18	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: rs727504883; hg19: chr8-102570811;