rs2235373

Variant names:

• chr1-209790458-G-A
• rs2235373
• NM_006147.4:c.1060+37C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-209790458-G-A
• chr1-209790458-G-C

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.1060+37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,602,858 control chromosomes in the GnomAD database, including 36,009 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4035 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31974 hom.)
• Consequence: IRF6 NM_006147.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.866
• Publications: 23 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=-0.88).
• BP6: Variant 1-209790458-G-A is Benign according to our data. Variant chr1-209790458-G-A is described in ClinVar as Benign. ClinVar VariationId is 1291060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.1060+37C>T		intron_variant	Intron 7 of 8	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.775+37C>T		intron_variant	Intron 5 of 6		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.1060+37C>T		intron_variant	Intron 7 of 8	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.1060+37C>T		intron_variant	Intron 7 of 9			ENSP00000512426.1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32795 AN: 152088 Hom.: 4031 Cov.: 33

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.236 AC: 59067 AN: 250666 AF XY: 0.230

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.483

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.198 AC: 287834 AN: 1450652 Hom.: 31974 Cov.: 30 AF XY: 0.200 AC XY: 144343 AN XY: 722336

African (AFR) AF: 0.236 AC: 7843 AN: 33216

American (AMR) AF: 0.343 AC: 15329 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3376 AN: 26064

East Asian (EAS) AF: 0.468 AC: 18541 AN: 39638

South Asian (SAS) AF: 0.292 AC: 25104 AN: 85880

European-Finnish (FIN) AF: 0.139 AC: 7421 AN: 53404

Middle Eastern (MID) AF: 0.164 AC: 749 AN: 4558

European-Non Finnish (NFE) AF: 0.179 AC: 197195 AN: 1103264

Other (OTH) AF: 0.205 AC: 12276 AN: 59926

GnomAD4 genome AF: 0.216 AC: 32817 AN: 152206 Hom.: 4035 Cov.: 33 AF XY: 0.219 AC XY: 16262 AN XY: 74418

African (AFR) AF: 0.235 AC: 9737 AN: 41504

American (AMR) AF: 0.324 AC: 4952 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 460 AN: 3472

East Asian (EAS) AF: 0.471 AC: 2441 AN: 5182

South Asian (SAS) AF: 0.307 AC: 1480 AN: 4816

European-Finnish (FIN) AF: 0.127 AC: 1350 AN: 10598

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11723 AN: 68018

Other (OTH) AF: 0.200 AC: 423 AN: 2114

Alfa AF: 0.178 Hom.: 491

Bravo AF: 0.229

Asia WGS AF: 0.329 AC: 1145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.45
PhyloP100		-0.87
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: rs2235373; hg19: chr1-209963803; COSMIC: COSV65418889; COSMIC: COSV65418889;