rs3779617

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024915.4(GRHL2):c.1243G>A(p.Val415Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,612,456 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0073 ( 33 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 269 hom. )

Consequence

GRHL2
NM_024915.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 10.0

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005496323).

BP6

Variant 8-101619683-G-A is Benign according to our data. Variant chr8-101619683-G-A is described in ClinVar as [Benign]. Clinvar id is 46215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-101619683-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GRHL2	NM_024915.4 linkuse as main transcript	c.1243G>A	p.Val415Ile	missense_variant	9/16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2 linkuse as main transcript	c.1195G>A	p.Val399Ile	missense_variant	9/16		NP_001317522.1
GRHL2	XM_011517306.4 linkuse as main transcript	c.1195G>A	p.Val399Ile	missense_variant	9/16		XP_011515608.1
GRHL2	XM_011517307.4 linkuse as main transcript	c.1243G>A	p.Val415Ile	missense_variant	9/16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1 linkuse as main transcript	c.1243G>A	p.Val415Ile	missense_variant	9/16		NM_024915.4	ENSP00000495564	P1	Q6ISB3-1
GRHL2	ENST00000395927.1 linkuse as main transcript	c.1195G>A	p.Val399Ile	missense_variant	9/16	2		ENSP00000379260		Q6ISB3-2

Frequencies

GnomAD3 genomes

AF:

0.00728

AC:

1108

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00871

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.0936

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0281

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.0135

AC:

3399

AN:

250920

Hom.:

123

AF XY:

0.0122

AC XY:

1656

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.00666

Gnomad EAS exome

AF:

0.100

Gnomad SAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.0293

Gnomad NFE exome

AF:

0.00199

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.00526

AC:

7678

AN:

1460240

Hom.:

269

Cov.:

AF XY:

0.00514

AC XY:

3732

AN XY:

726606

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.0139

Gnomad4 ASJ exome

AF:

0.00663

Gnomad4 EAS exome

AF:

0.0972

Gnomad4 SAS exome

AF:

0.00239

Gnomad4 FIN exome

AF:

0.0301

Gnomad4 NFE exome

AF:

0.000684

Gnomad4 OTH exome

AF:

0.00736

GnomAD4 genome

AF:

0.00725

AC:

1104

AN:

152216

Hom.:

Cov.:

AF XY:

0.00897

AC XY:

668

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00864

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.0934

Gnomad4 SAS

AF:

0.00539

Gnomad4 FIN

AF:

0.0281

Gnomad4 NFE

AF:

0.00157

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00461

Hom.:

Bravo

AF:

0.00663

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0129

AC:

1564

Asia WGS

AF:

0.0320

AC:

113

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Val415Ile in Exon 09 of GRHL2: This variant is not expected to have clinical sig nificance because it has been identified in 14.7% (25/170) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs3 779617). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

.;T;T

MetaRNN

Benign

0.0055

T;T;T

MetaSVM

Benign

-1.3

MutationAssessor

Uncertain

2.5

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.53

N;.;N

REVEL

Uncertain

0.29

Sift

Benign

0.41

T;.;T

Sift4G

Benign

0.40

T;.;T

Polyphen

0.88

P;P;.

Vest4

0.39

MPC

1.0

ClinPred

0.060

GERP RS

5.8

Varity_R

0.34

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over