rs3735713

chr8-101666744-G-Achr8-101666744-G-C

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.*41G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,158,186 control chromosomes in the GnomAD database, including 80,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11171 hom., cov: 31)
  • Exomes 𝑓: 0.36 (69449 hom.)
• Consequence: GRHL2 NM_024915.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.369

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 (BayesDel_noAF=-0.86).
• BP6: Variant 8-101666744-G-A is Benign according to our data. Variant chr8-101666744-G-A is described in ClinVar as [Benign]. Clinvar id is 1260503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL2	NM_024915.4	c.*41G>A		3_prime_UTR_variant	16/16	ENST00000646743.1
GRHL2	NM_001330593.2	c.*41G>A		3_prime_UTR_variant	16/16
GRHL2	XM_011517306.4	c.*41G>A		3_prime_UTR_variant	16/16
GRHL2	XM_011517307.4	c.1763+2226G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL2	ENST00000646743.1	c.*41G>A		3_prime_UTR_variant	16/16		NM_024915.4	P1
GRHL2	ENST00000395927.1	c.*41G>A		3_prime_UTR_variant	16/16	2

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57413 AN: 151816 Hom.: 11153 Cov.: 31

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.377

GnomAD3 exomes AF: 0.391 AC: 94688 AN: 242274 Hom.: 18994 AF XY: 0.393 AC XY: 51284 AN XY: 130558

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.350

Gnomad SAS exome AF: 0.541

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.346

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.362 AC: 364580 AN: 1006252 Hom.: 69449 Cov.: 14 AF XY: 0.368 AC XY: 191770 AN XY: 520616

Gnomad4 AFR exome AF: 0.424

Gnomad4 AMR exome AF: 0.456

Gnomad4 ASJ exome AF: 0.368

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.534

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.338

Gnomad4 OTH exome AF: 0.368

GnomAD4 genome AF: 0.378 AC: 57473 AN: 151934 Hom.: 11171 Cov.: 31 AF XY: 0.381 AC XY: 28274 AN XY: 74246

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.348

Gnomad4 SAS AF: 0.541

Gnomad4 FIN AF: 0.316

Gnomad4 NFE AF: 0.344

Gnomad4 OTH AF: 0.378

Alfa AF: 0.354 Hom.: 10314

Bravo AF: 0.382

Asia WGS AF: 0.516 AC: 1794 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Corneal dystrophy, posterior polymorphous, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2018

- -

Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Autosomal dominant nonsyndromic hearing loss 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.27
Dann	Benign	0.51

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

Other links and lift over

dbSNP: rs3735713; hg19: chr8-102678972; COSMIC: COSV52553097; COSMIC: COSV52553097;