dbSNP rs17317411: IRF6:c.*451A>G (chr1-209787969-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.309

Variant links:

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 links:

ENSG00000289700 (HGNC:):

ENSG00000289700 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 link	c.*451A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000367021.8	NP_006138.1	O14896-1G0Z349
IRF6	NM_001206696.2 link	c.*451A>G		3_prime_UTR_variant	Exon 7 of 7		NP_001193625.1	O14896-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021 link	c.*451A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_006147.4	ENSP00000355988.3		O14896-1
ENSG00000289700	ENST00000696133.1 link	c.1400+455A>G		intron_variant	Intron 9 of 9			ENSP00000512426.1		A0A8Q3SJ75

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16314

AN:

151928

Hom.:

1158

Cov.:

show subpopulations

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.:

AF XY:

0.121

AC XY:

3083

AN XY:

25434

show subpopulations

Gnomad4 AFR exome

AF:

0.0252

Gnomad4 AMR exome

AF:

0.0853

Gnomad4 ASJ exome

AF:

0.0746

Gnomad4 EAS exome

AF:

0.0340

Gnomad4 SAS exome

AF:

0.160

Gnomad4 FIN exome

AF:

0.101

Gnomad4 NFE exome

AF:

0.131

Gnomad4 OTH exome

AF:

0.0994

GnomAD4 genome

AF:

0.107

AC:

16306

AN:

152046

Hom.:

1155

Cov.:

AF XY:

0.106

AC XY:

7895

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0299

Gnomad4 AMR

AF:

0.114

Gnomad4 ASJ

AF:

0.0874

Gnomad4 EAS

AF:

0.0404

Gnomad4 SAS

AF:

0.187

Gnomad4 FIN

AF:

0.113

Gnomad4 NFE

AF:

0.152

Gnomad4 OTH

AF:

0.114

Alfa

AF:

0.127

Hom.:

602

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

LINK: link

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

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

DANN

Benign

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over