rs3735709

chr8-101543246-A-Gchr8-101543246-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024915.4(GRHL2):c.26A>G(p.Lys9Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,613,508 control chromosomes in the GnomAD database, including 688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (61 hom., cov: 32)
  • Exomes 𝑓: 0.026 (627 hom.)
• Consequence: GRHL2 NM_024915.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004516661).
• BP6: Variant 8-101543246-A-G is Benign according to our data. Variant chr8-101543246-A-G is described in ClinVar as [Benign]. Clinvar id is 46218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-101543246-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL2	NM_024915.4	c.26A>G	p.Lys9Arg	missense_variant	2/16	ENST00000646743.1
GRHL2	XM_011517307.4	c.26A>G	p.Lys9Arg	missense_variant	2/16
GRHL2	NM_001330593.2	c.-23A>G		5_prime_UTR_variant	2/16
GRHL2	XM_011517306.4	c.-23A>G		5_prime_UTR_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1	c.26A>G	p.Lys9Arg	missense_variant	2/16		NM_024915.4	P1
GRHL2	ENST00000472106.2	n.354A>G		non_coding_transcript_exon_variant	2/2	1
GRHL2	ENST00000395927.1	c.-23A>G		5_prime_UTR_variant	2/16	2

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3168 AN: 152170 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.0630

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0258 AC: 6473 AN: 251334 Hom.: 123 AF XY: 0.0258 AC XY: 3503 AN XY: 135846

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.0669

Gnomad SAS exome AF: 0.0213

Gnomad FIN exome AF: 0.0419

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0233

GnomAD4 exome AF: 0.0263 AC: 38380 AN: 1461220 Hom.: 627 Cov.: 30 AF XY: 0.0261 AC XY: 18999 AN XY: 726974

Gnomad4 AFR exome AF: 0.00326

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0572

Gnomad4 SAS exome AF: 0.0206

Gnomad4 FIN exome AF: 0.0414

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0234

GnomAD4 genome AF: 0.0208 AC: 3170 AN: 152288 Hom.: 61 Cov.: 32 AF XY: 0.0212 AC XY: 1577 AN XY: 74470

Gnomad4 AFR AF: 0.00455

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.0631

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.0433

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0248 Hom.: 92

Bravo AF: 0.0184

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0234 AC: 90

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0269 AC: 231

ExAC AF: 0.0251 AC: 3048

Asia WGS AF: 0.0300 AC: 103 AN: 3478

EpiCase AF: 0.0218

EpiControl AF: 0.0218

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Lys9Arg in Exon 02 of GRHL2: This variant is not expected to have clinical signi ficance because it has been identified in 2.8% (194/7020) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs3735709). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.14
Sift	Benign	0.49	T;.
Sift4G	Benign	0.27	T;.
Polyphen		0.85	P;P
Vest4		0.12
MPC		0.96
ClinPred		0.023	T
GERP RS		6.0
Varity_R		0.13
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3735709; hg19: chr8-102555474; COSMIC: COSV52552298;