rs34550163

Positions:

• chr8-101636911-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024915.4(GRHL2):​c.1500G>A​(p.Thr500=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000987 in 1,613,706 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (8 hom.)
• Consequence: GRHL2 NM_024915.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.791

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 8-101636911-G-A is Benign according to our data. Variant chr8-101636911-G-A is described in ClinVar as [Benign]. Clinvar id is 163648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-101636911-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.791 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00423 (643/152174) while in subpopulation AFR AF= 0.0144 (596/41514). AF 95% confidence interval is 0.0134. There are 5 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL2	NM_024915.4	c.1500G>A	p.Thr500=	synonymous_variant	12/16	ENST00000646743.1	NP_079191.2
GRHL2	NM_001330593.2	c.1452G>A	p.Thr484=	synonymous_variant	12/16		NP_001317522.1
GRHL2	XM_011517306.4	c.1452G>A	p.Thr484=	synonymous_variant	12/16		XP_011515608.1
GRHL2	XM_011517307.4	c.1500G>A	p.Thr500=	synonymous_variant	12/16		XP_011515609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL2	ENST00000646743.1	c.1500G>A	p.Thr500=	synonymous_variant	12/16		NM_024915.4	ENSP00000495564	P1
GRHL2	ENST00000395927.1	c.1452G>A	p.Thr484=	synonymous_variant	12/16	2		ENSP00000379260
GRHL2	ENST00000474338.1	n.142G>A		non_coding_transcript_exon_variant	1/4	3
GRHL2	ENST00000517674.5	n.155G>A		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 640 AN: 152056 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00125 AC: 313 AN: 251194 Hom.: 1 AF XY: 0.000928 AC XY: 126 AN XY: 135736

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000649 AC: 949 AN: 1461532 Hom.: 8 Cov.: 30 AF XY: 0.000561 AC XY: 408 AN XY: 727086

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00423 AC: 643 AN: 152174 Hom.: 5 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74400

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00508

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr500Thr in Exon 12 of GRHL2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 1.4% (53/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34550163). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.7
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34550163; hg19: chr8-102649139;