rs3735714

Variant names:

• chr8-101667094-C-T
• rs3735714
• NM_024915.4:c.*391C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024915.4(GRHL2):​c.*391C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 295,770 control chromosomes in the GnomAD database, including 22,517 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (11873 hom., cov: 32)
  • Exomes 𝑓: 0.37 (10644 hom.)
• Consequence: GRHL2 NM_024915.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.514 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.*391C>T		3_prime_UTR	Exon 16 of 16	NP_079191.2	Q6ISB3-1
	GRHL2	NM_001330593.2		c.*391C>T		3_prime_UTR	Exon 16 of 16	NP_001317522.1	Q6ISB3-2
	GRHL2	NM_001440448.1		c.*391C>T		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.*391C>T		3_prime_UTR	Exon 16 of 16	ENSP00000495564.1	Q6ISB3-1
	GRHL2	ENST00000395927.1	TSL:2	c.*391C>T		downstream_gene	N/A	ENSP00000379260.1	Q6ISB3-2
	GRHL2	ENST00000907653.1		c.*391C>T		downstream_gene	N/A	ENSP00000577712.1

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59074 AN: 151926 Hom.: 11855 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.384

GnomAD4 exome AF: 0.370 AC: 53116 AN: 143726 Hom.: 10644 Cov.: 0 AF XY: 0.379 AC XY: 28257 AN XY: 74582

African (AFR) AF: 0.449 AC: 2339 AN: 5214

American (AMR) AF: 0.427 AC: 3715 AN: 8696

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1360 AN: 3860

East Asian (EAS) AF: 0.398 AC: 3208 AN: 8068

South Asian (SAS) AF: 0.501 AC: 9918 AN: 19780

European-Finnish (FIN) AF: 0.301 AC: 1894 AN: 6286

Middle Eastern (MID) AF: 0.367 AC: 204 AN: 556

European-Non Finnish (NFE) AF: 0.331 AC: 27635 AN: 83468

Other (OTH) AF: 0.365 AC: 2843 AN: 7798

GnomAD4 genome AF: 0.389 AC: 59136 AN: 152044 Hom.: 11873 Cov.: 32 AF XY: 0.392 AC XY: 29092 AN XY: 74302

African (AFR) AF: 0.450 AC: 18672 AN: 41456

American (AMR) AF: 0.422 AC: 6461 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1360 AN: 3470

East Asian (EAS) AF: 0.403 AC: 2071 AN: 5142

South Asian (SAS) AF: 0.531 AC: 2561 AN: 4822

European-Finnish (FIN) AF: 0.318 AC: 3365 AN: 10576

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

European-Non Finnish (NFE) AF: 0.346 AC: 23519 AN: 67968

Other (OTH) AF: 0.384 AC: 810 AN: 2108

Alfa AF: 0.368 Hom.: 6403

Bravo AF: 0.395

Asia WGS AF: 0.529 AC: 1840 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.87
DANN	Benign	0.58
PhyloP100		-1.1
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: rs3735714; hg19: chr8-102679322;