1-209792242-G-C

Variant names:

• chr1-209792242-G-C
• rs2235375
• NM_006147.4:c.667+27C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006147.4(IRF6):​c.667+27C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,604,424 control chromosomes in the GnomAD database, including 120,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10639 hom., cov: 33)
  • Exomes 𝑓: 0.38 (109958 hom.)
• Consequence: IRF6 NM_006147.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0730
• Publications: 37 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• IRF6-related condition

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-209792242-G-C is Benign according to our data. Variant chr1-209792242-G-C is described in ClinVar as Benign. ClinVar VariationId is 259926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.667+27C>G		intron_variant	Intron 6 of 8	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.382+27C>G		intron_variant	Intron 4 of 6		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.667+27C>G		intron_variant	Intron 6 of 8	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.667+27C>G		intron_variant	Intron 6 of 9			ENSP00000512426.1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55841 AN: 151974 Hom.: 10636 Cov.: 33

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.360

GnomAD2 exomes AF: 0.410 AC: 103035 AN: 251268 AF XY: 0.403

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.572

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.373

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.385 AC: 558705 AN: 1452332 Hom.: 109958 Cov.: 31 AF XY: 0.385 AC XY: 278146 AN XY: 723114

African (AFR) AF: 0.283 AC: 9422 AN: 33286

American (AMR) AF: 0.550 AC: 24583 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 8027 AN: 26086

East Asian (EAS) AF: 0.568 AC: 22498 AN: 39638

South Asian (SAS) AF: 0.414 AC: 35602 AN: 86068

European-Finnish (FIN) AF: 0.379 AC: 20218 AN: 53370

Middle Eastern (MID) AF: 0.321 AC: 1844 AN: 5742

European-Non Finnish (NFE) AF: 0.375 AC: 414032 AN: 1103342

Other (OTH) AF: 0.374 AC: 22479 AN: 60082

GnomAD4 genome AF: 0.367 AC: 55864 AN: 152092 Hom.: 10639 Cov.: 33 AF XY: 0.371 AC XY: 27592 AN XY: 74330

African (AFR) AF: 0.288 AC: 11946 AN: 41476

American (AMR) AF: 0.494 AC: 7556 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1109 AN: 3468

East Asian (EAS) AF: 0.565 AC: 2920 AN: 5170

South Asian (SAS) AF: 0.432 AC: 2083 AN: 4826

European-Finnish (FIN) AF: 0.366 AC: 3872 AN: 10578

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25163 AN: 67976

Other (OTH) AF: 0.356 AC: 751 AN: 2108

Alfa AF: 0.273 Hom.: 1041

Bravo AF: 0.374

Asia WGS AF: 0.428 AC: 1492 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant popliteal pterygium syndrome Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.4
DANN	Benign	0.52
PhyloP100		0.073
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2235375; hg19: chr1-209965587; COSMIC: COSV65418892;