rs2235371

Variant names:

• chr1-209790735-C-T
• rs2235371
• NM_006147.4:c.820G>A
• IRF6 p.Val274Ile

Germline classificationCancer classification (beta)

Variant summary

Our verdict is

Benign

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received -11 ACMG points: 1P and 12B. BA1PP2BP6_Strong

The NM_006147.4(IRF6):c.820G>A (p.Val274Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.037 (AC=59,670) in the gnomAD database across 1,614,178 control chromosomes, including 6,385 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.407. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.045 (802 hom., cov: 33)
  • Exomes 𝑓: 0.036 (5583 hom.)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.84
• Publications: 131 publications found

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]

IRF6 Gene-Disease associations (from GenCC):

• autosomal dominant popliteal pterygium syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• IRF6-related condition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• van der Woude syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• popliteal pterygium syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• van der Woude syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofacial cleft 6, susceptibility to

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000289700 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -11 ACMG points.

• PP2: Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 3.898). ClinVar shows strong pathogenic missense enrichment: 64 P/LP and 10 B/LB missense entries (ratio 6.4×).
• BP6: ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4075 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006147.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	NM_006147.4	MANE Select	c.820G>A	p.Val274Ile	missense	Exon 7 of 9	NP_006138.1	G0Z349
	IRF6	NM_001206696.2		c.535G>A	p.Val179Ile	missense	Exon 5 of 7	NP_001193625.1	O14896-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	ENST00000367021.8	TSL:1 MANE Select	c.820G>A	p.Val274Ile	missense	Exon 7 of 9	ENSP00000355988.3	O14896-1
	ENSG00000289700	ENST00000696133.1		c.820G>A	p.Val274Ile	missense	Exon 7 of 10	ENSP00000512426.1	A0A8Q3SJ75
	IRF6	ENST00000863915.1		c.820G>A	p.Val274Ile	missense	Exon 6 of 8	ENSP00000533974.1

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6800 AN: 152176 Hom.: 797 Cov.: 33

Gnomad AFR AF: 0.00709

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0368

GnomAD2 exomes AF: 0.0867 AC: 21729 AN: 250644 AF XY: 0.0783

Gnomad AFR exome AF: 0.00579

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.0183

Gnomad EAS exome AF: 0.416

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0563

GnomAD4 exome AF: 0.0362 AC: 52859 AN: 1461884 Hom.: 5583 Cov.: 33 AF XY: 0.0362 AC XY: 26347 AN XY: 727246

African (AFR) AF: 0.00490 AC: 164 AN: 33480

American (AMR) AF: 0.253 AC: 11331 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 491 AN: 26136

East Asian (EAS) AF: 0.413 AC: 16386 AN: 39698

South Asian (SAS) AF: 0.0793 AC: 6838 AN: 86258

European-Finnish (FIN) AF: 0.0146 AC: 781 AN: 53414

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.0128 AC: 14189 AN: 1112010

Other (OTH) AF: 0.0435 AC: 2625 AN: 60396

GnomAD4 genome AF: 0.0447 AC: 6811 AN: 152294 Hom.: 802 Cov.: 33 AF XY: 0.0512 AC XY: 3812 AN XY: 74472

African (AFR) AF: 0.00707 AC: 294 AN: 41576

American (AMR) AF: 0.182 AC: 2776 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3466

East Asian (EAS) AF: 0.406 AC: 2096 AN: 5162

South Asian (SAS) AF: 0.0915 AC: 442 AN: 4828

European-Finnish (FIN) AF: 0.0125 AC: 133 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 909 AN: 68022

Other (OTH) AF: 0.0369 AC: 78 AN: 2114

Alfa AF: 0.0327 Hom.: 2053

Bravo AF: 0.0572

Asia WGS AF: 0.185 AC: 643 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0123

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.422 AC: 51815 AN: 122800

Turkish Variome AF: 0.0288 AC: 193 AN: 6702 Hom.: 5

WBBC (Westlake BioBank for Chinese) pilot AF: 0.416 AC: 3725 AN: 8960 Hom.: 777

ABraOM SABE-WGS-1171 AF: 0.0576 AC: 135 AN: 2342 Hom.: 11

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Orofacial cleft 6, susceptibility to (1)
-	-	1	Van der Woude syndrome 1 (1)
-	-	1	Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.019	D
Varity_R		0.23
gMVP		0.10
Mutation Taster		=97/3	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2235371;

hg19: chr1-209964080;

COSMIC: COSV65418781;

COSMIC: COSV65418781;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar