rs41303263

Positions:

• chr1-209790796-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006147.4(IRF6):​c.759T>C​(p.Tyr253=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,614,166 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (8 hom.)
• Consequence: IRF6 NM_006147.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0130

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 1-209790796-A-G is Benign according to our data. Variant chr1-209790796-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.013 with no splicing effect.
• BS2: High AC in GnomAd4 at 360 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4	c.759T>C	p.Tyr253=	synonymous_variant	7/9	ENST00000367021.8
IRF6	NM_001206696.2	c.474T>C	p.Tyr158=	synonymous_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.759T>C	p.Tyr253=	synonymous_variant	7/9	1	NM_006147.4	P1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00252 AC: 633 AN: 250982 Hom.: 0 AF XY: 0.00257 AC XY: 349 AN XY: 135634

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.00315

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00408

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00374 AC: 5470 AN: 1461846 Hom.: 8 Cov.: 33 AF XY: 0.00363 AC XY: 2640 AN XY: 727232

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00219

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00450

Gnomad4 OTH exome AF: 0.00272

GnomAD4 genome AF: 0.00236 AC: 360 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.00230 AC XY: 171 AN XY: 74490

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00392

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00254

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely 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 15, 2024

- -

Orofacial cleft 6, susceptibility to Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Van der Woude syndrome 1 Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely 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	-0.64
CADD	Benign	5.4
DANN	Benign	0.75

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: rs41303263; hg19: chr1-209964141; COSMIC: COSV65419851;