rs2013162

chr1-209795339-C-Achr1-209795339-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006147.4(IRF6):c.459G>T(p.Ser153=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,602 control chromosomes in the GnomAD database, including 121,060 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10526 hom., cov: 32)
  • Exomes 𝑓: 0.39 (110534 hom.)
• Consequence: IRF6 NM_006147.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.72

Genes affected

IRF6 (HGNC:6121): (interferon regulatory factor 6) This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly-conserved N-terminal helix-turn-helix DNA-binding domain and a less conserved C-terminal protein-binding domain. The encoded protein may be a transcriptional activator. Mutations in this gene can cause van der Woude syndrome and popliteal pterygium syndrome. Mutations in this gene are also associated with non-syndromic orofacial cleft type 6. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2011]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 1-209795339-C-A is Benign according to our data. Variant chr1-209795339-C-A is described in ClinVar as [Benign]. Clinvar id is 259925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-209795339-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4	c.459G>T	p.Ser153=	synonymous_variant	5/9	ENST00000367021.8
IRF6	NM_001206696.2	c.174G>T	p.Ser58=	synonymous_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.459G>T	p.Ser153=	synonymous_variant	5/9	1	NM_006147.4	P1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55499 AN: 151972 Hom.: 10523 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.361

GnomAD3 exomes AF: 0.410 AC: 103019 AN: 251410 Hom.: 22367 AF XY: 0.403 AC XY: 54724 AN XY: 135878

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.560

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.573

Gnomad SAS exome AF: 0.416

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.373

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.385 AC: 562690 AN: 1461512 Hom.: 110534 Cov.: 48 AF XY: 0.385 AC XY: 279808 AN XY: 727082

Gnomad4 AFR exome AF: 0.276

Gnomad4 AMR exome AF: 0.552

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.569

Gnomad4 SAS exome AF: 0.412

Gnomad4 FIN exome AF: 0.379

Gnomad4 NFE exome AF: 0.376

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.365 AC: 55523 AN: 152090 Hom.: 10526 Cov.: 32 AF XY: 0.369 AC XY: 27445 AN XY: 74322

Gnomad4 AFR AF: 0.280

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.320

Gnomad4 EAS AF: 0.566

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.370

Gnomad4 OTH AF: 0.357

Alfa AF: 0.359 Hom.: 18386

Bravo AF: 0.371

Asia WGS AF: 0.425 AC: 1480 AN: 3478

EpiCase AF: 0.365

EpiControl AF: 0.362

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Orofacial cleft 6, susceptibility to Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Autosomal dominant popliteal pterygium syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Van der Woude syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	0.29
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2013162; hg19: chr1-209968684; COSMIC: COSV65418898; COSMIC: COSV65418898;