rs3824090

Variant names:

• chr8-101666988-C-T
• rs3824090
• NM_024915.4:c.*285C>T

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.*285C>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 0.236 in 523,474 control chromosomes in the GnomAD database, including 15,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4562 hom., cov: 32)
  • Exomes 𝑓: 0.23 (10565 hom.)
• Consequence: GRHL2 NM_024915.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.284
• Publications: 7 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):

• autosomal dominant nonsyndromic hearing loss 28

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, 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=-0.85).
• BP6: Variant 8-101666988-C-T is Benign according to our data. Variant chr8-101666988-C-T is described in ClinVar as Benign. ClinVar VariationId is 1261948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.*285C>T		3_prime_UTR_variant	Exon 16 of 16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.*285C>T		3_prime_UTR_variant	Exon 16 of 16		NP_001317522.1
GRHL2	NM_001440448.1	c.*285C>T		3_prime_UTR_variant	Exon 16 of 16		NP_001427377.1
GRHL2	NM_001440447.1	c.1763+2470C>T		intron_variant	Intron 15 of 15		NP_001427376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.*285C>T		3_prime_UTR_variant	Exon 16 of 16		NM_024915.4	ENSP00000495564.1
GRHL2	ENST00000395927.1	c.*285C>T		downstream_gene_variant		2		ENSP00000379260.1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36608 AN: 151816 Hom.: 4562 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.234 AC: 86758 AN: 371540 Hom.: 10565 Cov.: 0 AF XY: 0.237 AC XY: 46540 AN XY: 196760

African (AFR) AF: 0.277 AC: 3010 AN: 10856

American (AMR) AF: 0.315 AC: 5178 AN: 16426

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 2576 AN: 11266

East Asian (EAS) AF: 0.257 AC: 6103 AN: 23748

South Asian (SAS) AF: 0.293 AC: 12986 AN: 44308

European-Finnish (FIN) AF: 0.211 AC: 4623 AN: 21908

Middle Eastern (MID) AF: 0.206 AC: 325 AN: 1580

European-Non Finnish (NFE) AF: 0.214 AC: 47052 AN: 220176

Other (OTH) AF: 0.231 AC: 4905 AN: 21272

GnomAD4 genome AF: 0.241 AC: 36627 AN: 151934 Hom.: 4562 Cov.: 32 AF XY: 0.242 AC XY: 17990 AN XY: 74244

African (AFR) AF: 0.281 AC: 11651 AN: 41416

American (AMR) AF: 0.277 AC: 4224 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 803 AN: 3470

East Asian (EAS) AF: 0.246 AC: 1267 AN: 5140

South Asian (SAS) AF: 0.285 AC: 1366 AN: 4800

European-Finnish (FIN) AF: 0.201 AC: 2127 AN: 10562

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14553 AN: 67958

Other (OTH) AF: 0.227 AC: 480 AN: 2110

Alfa AF: 0.219 Hom.: 4521

Bravo AF: 0.247

Asia WGS AF: 0.262 AC: 915 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.1
DANN	Benign	0.61
PhyloP100		-0.28
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: rs3824090; hg19: chr8-102679216;