rs116396279

chr1-24344928-A-G

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.1451A>G(p.Asn484Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,150 control chromosomes in the GnomAD database, including 1,470 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 0.033 (104 hom., cov: 31)
  • Exomes 𝑓: 0.040 (1366 hom.)
• Consequence: GRHL3 NM_198173.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.114

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=0.0019854307).
• BP6: Variant 1-24344928-A-G is Benign according to our data. Variant chr1-24344928-A-G is described in ClinVar as [Benign]. Clinvar id is 465249.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 = 0.0329 (4995/151784) while in subpopulation NFE AF= 0.0473 (3209/67866). AF 95% confidence interval is 0.0459. There are 104 homozygotes in gnomad4. There are 2455 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 4992 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL3	NM_198173.3	c.1451A>G	p.Asn484Ser	missense_variant	12/16	ENST00000361548.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL3	ENST00000361548.9	c.1451A>G	p.Asn484Ser	missense_variant	12/16	1	NM_198173.3	P1

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 4992 AN: 151666 Hom.: 104 Cov.: 31

Gnomad AFR AF: 0.00779

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0299

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00892

Gnomad FIN AF: 0.0738

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0473

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0335 AC: 8420 AN: 251056 Hom.: 225 AF XY: 0.0334 AC XY: 4530 AN XY: 135716

Gnomad AFR exome AF: 0.00764

Gnomad AMR exome AF: 0.0223

Gnomad ASJ exome AF: 0.0367

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0102

Gnomad FIN exome AF: 0.0674

Gnomad NFE exome AF: 0.0454

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0404 AC: 59041 AN: 1461366 Hom.: 1366 Cov.: 33 AF XY: 0.0396 AC XY: 28823 AN XY: 727020

Gnomad4 AFR exome AF: 0.00627

Gnomad4 AMR exome AF: 0.0230

Gnomad4 ASJ exome AF: 0.0357

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0717

Gnomad4 NFE exome AF: 0.0448

Gnomad4 OTH exome AF: 0.0357

GnomAD4 genome AF: 0.0329 AC: 4995 AN: 151784 Hom.: 104 Cov.: 31 AF XY: 0.0331 AC XY: 2455 AN XY: 74168

Gnomad4 AFR AF: 0.00777

Gnomad4 AMR AF: 0.0298

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00914

Gnomad4 FIN AF: 0.0738

Gnomad4 NFE AF: 0.0473

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0423 Hom.: 177

Bravo AF: 0.0287

TwinsUK AF: 0.0502 AC: 186

ALSPAC AF: 0.0490 AC: 189

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0460 AC: 396

ExAC AF: 0.0324 AC: 3932

Asia WGS AF: 0.00578 AC: 20 AN: 3476

EpiCase AF: 0.0450

EpiControl AF: 0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GRHL3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Van der Woude syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.3
Dann	Benign	0.85
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.73	T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L;L;.;.
MutationTaster	Benign	0.71	D;D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.030	N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.68	T;T;T;T
Sift4G	Benign	0.79	T;T;T;T
Polyphen		0.0010	.;.;.;B
Vest4		0.21
MPC		0.29
ClinPred		0.0011	T
GERP RS		-0.14
Varity_R		0.028
gMVP		0.16

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: rs116396279; hg19: chr1-24671418;