rs145518215

Positions:

chr8-101558507-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6_Moderate

The NM_024915.4(GRHL2):c.373T>G(p.Ser125Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GRHL2
NM_024915.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.44

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 Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23418668).

BP6

Variant 8-101558507-T-G is Benign according to our data. Variant chr8-101558507-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 46219.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GRHL2	NM_024915.4 linkuse as main transcript	c.373T>G	p.Ser125Ala	missense_variant	4/16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2 linkuse as main transcript	c.325T>G	p.Ser109Ala	missense_variant	4/16		NP_001317522.1
GRHL2	XM_011517306.4 linkuse as main transcript	c.325T>G	p.Ser109Ala	missense_variant	4/16		XP_011515608.1
GRHL2	XM_011517307.4 linkuse as main transcript	c.373T>G	p.Ser125Ala	missense_variant	4/16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1 linkuse as main transcript	c.373T>G	p.Ser125Ala	missense_variant	4/16		NM_024915.4	ENSP00000495564	P1	Q6ISB3-1
GRHL2	ENST00000395927.1 linkuse as main transcript	c.325T>G	p.Ser109Ala	missense_variant	4/16	2		ENSP00000379260		Q6ISB3-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251454

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 11, 2012

Ser125Ala in Exon 4 of GRHL2: This variant has been identified in 0.02% (1/4406) of African American chromosomes in a broad population by the NHLBI Exome sequen cing project (http://evs.gs.washington.edu/EVS/; dbSNP rs145518215); however, th is frequency is not high enough to rule out a pathogenic role. Computational ana lyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, an d SIFT) suggest that the Ser125Ala variant is not likely to impact the protein, in part due to the fact that the Ser125 residue is not conserved in mammals (thr ee have a cysteine despite nearby conservation). These data, combined with ident ification of this variant in a family without dominant hearing loss, the known i nheritance pattern for pathogenic variants in this gene, suggests that this vari ant is more likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

.;T;T

M_CAP

Benign

0.0086

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;M;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

N;.;N

REVEL

Benign

0.12

Sift

Benign

0.18

T;.;T

Sift4G

Benign

0.19

T;.;T

Polyphen

0.85

P;P;.

Vest4

0.45

MVP

0.068

MPC

0.39

ClinPred

0.31

GERP RS

4.1

Varity_R

0.10

gMVP

0.28

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