chr1-209787969-T-C

Variant names:

• chr1-209787969-T-C
• rs17317411
• NM_006147.4:c.*451A>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.*451A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 200,636 control chromosomes in the GnomAD database, including 1,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1155 hom., cov: 32)
  • Exomes 𝑓: 0.12 (464 hom.)
• Consequence: IRF6 NM_006147.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.309
• Publications: 7 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=-0.75).
• BP6: Variant 1-209787969-T-C is Benign according to our data. Variant chr1-209787969-T-C is described in ClinVar as Benign. ClinVar VariationId is 295199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.*451A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.*451A>G		3_prime_UTR_variant	Exon 7 of 7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.*451A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.1400+455A>G		intron_variant	Intron 9 of 9			ENSP00000512426.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16314 AN: 151928 Hom.: 1158 Cov.: 32

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0874

Gnomad EAS AF: 0.0403

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.116

GnomAD4 exome AF: 0.120 AC: 5833 AN: 48590 Hom.: 464 Cov.: 0 AF XY: 0.121 AC XY: 3083 AN XY: 25434

African (AFR) AF: 0.0252 AC: 20 AN: 794

American (AMR) AF: 0.0853 AC: 304 AN: 3562

Ashkenazi Jewish (ASJ) AF: 0.0746 AC: 73 AN: 978

East Asian (EAS) AF: 0.0340 AC: 88 AN: 2590

South Asian (SAS) AF: 0.160 AC: 1064 AN: 6660

European-Finnish (FIN) AF: 0.101 AC: 236 AN: 2328

Middle Eastern (MID) AF: 0.0616 AC: 9 AN: 146

European-Non Finnish (NFE) AF: 0.131 AC: 3791 AN: 29038

Other (OTH) AF: 0.0994 AC: 248 AN: 2494

GnomAD4 genome AF: 0.107 AC: 16306 AN: 152046 Hom.: 1155 Cov.: 32 AF XY: 0.106 AC XY: 7895 AN XY: 74316

African (AFR) AF: 0.0299 AC: 1242 AN: 41498

American (AMR) AF: 0.114 AC: 1743 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0874 AC: 303 AN: 3466

East Asian (EAS) AF: 0.0404 AC: 209 AN: 5172

South Asian (SAS) AF: 0.187 AC: 900 AN: 4824

European-Finnish (FIN) AF: 0.113 AC: 1187 AN: 10536

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10303 AN: 67972

Other (OTH) AF: 0.114 AC: 241 AN: 2108

Alfa AF: 0.127 Hom.: 700

Bravo AF: 0.100

Asia WGS AF: 0.105 AC: 369 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orofacial cleft 6, susceptibility to Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Van der Woude syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		0.31
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: rs17317411; hg19: chr1-209961314; COSMIC: COSV54213602; COSMIC: COSV54213602;