rs3735713

Variant names:

• chr8-101666744-G-A
• rs3735713
• NM_024915.4:c.*41G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-101666744-G-A
• chr8-101666744-G-C

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: -0.369
• Publications: 18 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):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 28

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), 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: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024915.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	NM_024915.4	MANE Select	c.*41G>A		3_prime_UTR	Exon 16 of 16	NP_079191.2	Q6ISB3-1
	GRHL2	NM_001330593.2		c.*41G>A		3_prime_UTR	Exon 16 of 16	NP_001317522.1	Q6ISB3-2
	GRHL2	NM_001440448.1		c.*41G>A		3_prime_UTR	Exon 16 of 16	NP_001427377.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL2	ENST00000646743.1	MANE Select	c.*41G>A		3_prime_UTR	Exon 16 of 16	ENSP00000495564.1	Q6ISB3-1
	GRHL2	ENST00000395927.1	TSL:2	c.*41G>A		3_prime_UTR	Exon 16 of 16	ENSP00000379260.1	Q6ISB3-2
	GRHL2	ENST00000907653.1		c.*41G>A		3_prime_UTR	Exon 14 of 14	ENSP00000577712.1

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

GnomAD2 exomes AF: 0.391 AC: 94688 AN: 242274 AF XY: 0.393

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 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

African (AFR) AF: 0.424 AC: 10469 AN: 24666

American (AMR) AF: 0.456 AC: 19825 AN: 43432

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 8522 AN: 23180

East Asian (EAS) AF: 0.356 AC: 13410 AN: 37630

South Asian (SAS) AF: 0.534 AC: 40722 AN: 76258

European-Finnish (FIN) AF: 0.322 AC: 17047 AN: 52978

Middle Eastern (MID) AF: 0.390 AC: 1813 AN: 4646

European-Non Finnish (NFE) AF: 0.338 AC: 236080 AN: 698064

Other (OTH) AF: 0.368 AC: 16692 AN: 45398

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

African (AFR) AF: 0.424 AC: 17568 AN: 41444

American (AMR) AF: 0.415 AC: 6331 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1346 AN: 3464

East Asian (EAS) AF: 0.348 AC: 1784 AN: 5132

South Asian (SAS) AF: 0.541 AC: 2604 AN: 4812

European-Finnish (FIN) AF: 0.316 AC: 3340 AN: 10568

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23387 AN: 67932

Other (OTH) AF: 0.378 AC: 796 AN: 2106

Alfa AF: 0.358 Hom.: 13639

Bravo AF: 0.382

Asia WGS AF: 0.516 AC: 1794 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 28 (1)
-	-	1	Corneal dystrophy, posterior polymorphous, 4 (1)
-	-	1	Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.27
DANN	Benign	0.51
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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