rs34637004

Positions:

• chr1-24336694-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198173.3(GRHL3):​c.479T>C​(p.Val160Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,614,096 control chromosomes in the GnomAD database, including 1,490 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (119 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1371 hom.)
• Consequence: GRHL3 NM_198173.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.288

Genes affected

GRHL3 (HGNC:25839): (grainyhead like transcription factor 3) This gene encodes a member of the grainyhead family of transcription factors. The encoded protein may function as a transcription factor during development, and has been shown to stimulate migration of endothelial cells. Multiple transcript variants encoding distinct isoforms have been identified for this gene.[provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018627644).
• BP6: Variant 1-24336694-T-C is Benign according to our data. Variant chr1-24336694-T-C is described in ClinVar as [Benign]. Clinvar id is 465250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0335 (5104/152286) while in subpopulation NFE AF= 0.0462 (3143/68016). AF 95% confidence interval is 0.0449. There are 119 homozygotes in gnomad4. There are 2573 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 5104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL3	NM_198173.3	c.479T>C	p.Val160Ala	missense_variant	4/16	ENST00000361548.9	NP_937816.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL3	ENST00000361548.9	c.479T>C	p.Val160Ala	missense_variant	4/16	1	NM_198173.3	ENSP00000354943	P1

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 5101 AN: 152168 Hom.: 119 Cov.: 32

Gnomad AFR AF: 0.00755

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0912

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0462

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0339 AC: 8531 AN: 251324 Hom.: 247 AF XY: 0.0339 AC XY: 4612 AN XY: 135848

Gnomad AFR exome AF: 0.00696

Gnomad AMR exome AF: 0.0204

Gnomad ASJ exome AF: 0.0388

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.0790

Gnomad NFE exome AF: 0.0446

Gnomad OTH exome AF: 0.0373

GnomAD4 exome AF: 0.0398 AC: 58159 AN: 1461810 Hom.: 1371 Cov.: 32 AF XY: 0.0391 AC XY: 28400 AN XY: 727212

Gnomad4 AFR exome AF: 0.00597

Gnomad4 AMR exome AF: 0.0212

Gnomad4 ASJ exome AF: 0.0385

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.0841

Gnomad4 NFE exome AF: 0.0435

Gnomad4 OTH exome AF: 0.0348

GnomAD4 genome AF: 0.0335 AC: 5104 AN: 152286 Hom.: 119 Cov.: 32 AF XY: 0.0346 AC XY: 2573 AN XY: 74460

Gnomad4 AFR AF: 0.00753

Gnomad4 AMR AF: 0.0286

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0912

Gnomad4 NFE AF: 0.0462

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0409 Hom.: 223

Bravo AF: 0.0280

TwinsUK AF: 0.0499 AC: 185

ALSPAC AF: 0.0480 AC: 185

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0450 AC: 387

ExAC AF: 0.0327 AC: 3970

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0449

EpiControl AF: 0.0439

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

GRHL3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Van der Woude syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.070	.;T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.56	T;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.55	N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.70	N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.51	T;T;T;T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.0	.;.;.;B
Vest4		0.21
MPC		0.44
ClinPred		0.0049	T
GERP RS		3.7
Varity_R		0.053
gMVP		0.22

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: rs34637004; hg19: chr1-24663184;