Genetic Variant IRF6:c.-397G>C (chr1-209806268-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006147.4(IRF6):c.-397G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 152,272 control chromosomes in the GnomAD database, including 12,836 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.40 ( 12825 hom., cov: 33)

Exomes 𝑓: 0.43 ( 11 hom. )

Consequence

IRF6
NM_006147.4 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.925

Publications

10 publications found

Variant links:

COSMIC-nc: COSV65418968

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)

IRF6 links:

ENSG00000289700 (HGNC:):

ENSG00000289700 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4 link	c.-397G>C		upstream_gene_variant		ENST00000367021.8	NP_006138.1	O14896-1G0Z349
IRF6	NM_001206696.2 link	c.-433G>C		upstream_gene_variant			NP_001193625.1	O14896-2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
IRF6	ENST00000367021.8 link	c.-397G>C	upstream_gene_variant	1	NM_006147.4	ENSP00000355988.3	O14896-1
ENSG00000289700	ENST00000696133.1 link	c.-397G>C	upstream_gene_variant			ENSP00000512426.1	A0A8Q3SJ75
IRF6	ENST00000542854.5 link	c.-433G>C	upstream_gene_variant	2		ENSP00000440532.1	O14896-2
IRF6	ENST00000696134.1 link	n.-397G>C	upstream_gene_variant			ENSP00000512427.1	A0A8Q3WL17

Frequencies

GnomAD3 genomes

AF:

0.403

AC:

61278

AN:

152040

Hom.:

12826

Cov.:

show subpopulations

Gnomad AFR

AF:

0.286

Gnomad AMI

AF:

0.394

Gnomad AMR

AF:

0.515

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.568

Gnomad SAS

AF:

0.474

Gnomad FIN

AF:

0.456

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.428

Gnomad OTH

AF:

0.390

GnomAD4 exome

AF:

0.430

AC:

AN:

114

Hom.:

AF XY:

0.477

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.750

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.333

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.450

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.403

AC:

61294

AN:

152158

Hom.:

12825

Cov.:

AF XY:

0.408

AC XY:

30358

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.286

AC:

11871

AN:

41524

American (AMR)

AF:

0.515

AC:

7881

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.325

AC:

1127

AN:

3472

East Asian (EAS)

AF:

0.567

AC:

2926

AN:

5162

South Asian (SAS)

AF:

0.474

AC:

2291

AN:

4830

European-Finnish (FIN)

AF:

0.456

AC:

4825

AN:

10578

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.428

AC:

29084

AN:

67974

Other (OTH)

AF:

0.385

AC:

814

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1927

3854

5780

7707

9634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

594

1188

1782

2376

2970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.286

Hom.:

779

Bravo

AF:

0.400

Asia WGS

AF:

0.444

AC:

1546

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

9.3

(source)

DANN

Benign

0.44

PhyloP100

0.93

PromoterAI

-0.0068

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over