1-209795339-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006147.4(IRF6):c.459G>T(p.Ser153Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,602 control chromosomes in the GnomAD database, including 121,060 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10526 hom., cov: 32)

Exomes 𝑓: 0.39 ( 110534 hom. )

Consequence

IRF6
NM_006147.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.72

Publications

70 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant popliteal pterygium syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
IRF6-related condition
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
van der Woude syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 1-209795339-C-A is Benign according to our data. Variant chr1-209795339-C-A is described in ClinVar as Benign. ClinVar VariationId is 259925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.72 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006147.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	NM_006147.4	MANE Select	c.459G>T	p.Ser153Ser	synonymous	Exon 5 of 9	NP_006138.1	G0Z349
	IRF6	NM_001206696.2		c.174G>T	p.Ser58Ser	synonymous	Exon 3 of 7	NP_001193625.1	O14896-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRF6	ENST00000367021.8	TSL:1 MANE Select	c.459G>T	p.Ser153Ser	synonymous	Exon 5 of 9	ENSP00000355988.3	O14896-1
ENSG00000289700	ENST00000696133.1		c.459G>T	p.Ser153Ser	synonymous	Exon 5 of 10	ENSP00000512426.1	A0A8Q3SJ75
IRF6	ENST00000863915.1		c.459G>T	p.Ser153Ser	synonymous	Exon 4 of 8	ENSP00000533974.1

Frequencies

GnomAD3 genomes

AF:

0.365

AC:

55499

AN:

151972

Hom.:

10523

Cov.:

show subpopulations

Gnomad AFR

AF:

0.280

Gnomad AMI

AF:

0.395

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.320

Gnomad EAS

AF:

0.567

Gnomad SAS

AF:

0.430

Gnomad FIN

AF:

0.366

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.370

Gnomad OTH

AF:

0.361

GnomAD2 exomes

AF:

0.410

AC:

103019

AN:

251410

AF XY:

0.403

show subpopulations

Gnomad AFR exome

AF:

0.275

Gnomad AMR exome

AF:

0.560

Gnomad ASJ exome

AF:

0.309

Gnomad EAS exome

AF:

0.573

Gnomad FIN exome

AF:

0.373

Gnomad NFE exome

AF:

0.373

Gnomad OTH exome

AF:

0.372

GnomAD4 exome

AF:

0.385

AC:

562690

AN:

1461512

Hom.:

110534

Cov.:

AF XY:

0.385

AC XY:

279808

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.276

AC:

9254

AN:

33474

American (AMR)

AF:

0.552

AC:

24694

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

8046

AN:

26130

East Asian (EAS)

AF:

0.569

AC:

22579

AN:

39700

South Asian (SAS)

AF:

0.412

AC:

35567

AN:

86250

European-Finnish (FIN)

AF:

0.379

AC:

20221

AN:

53402

Middle Eastern (MID)

AF:

0.322

AC:

1856

AN:

5768

European-Non Finnish (NFE)

AF:

0.376

AC:

417865

AN:

1111684

Other (OTH)

AF:

0.374

AC:

22608

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

20633

41266

61899

82532

103165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13336

26672

40008

53344

66680

<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:

0.365

AC:

55523

AN:

152090

Hom.:

10526

Cov.:

AF XY:

0.369

AC XY:

27445

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.280

AC:

11614

AN:

41504

American (AMR)

AF:

0.495

AC:

7567

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.320

AC:

1109

AN:

3468

East Asian (EAS)

AF:

0.566

AC:

2925

AN:

5170

South Asian (SAS)

AF:

0.430

AC:

2073

AN:

4820

European-Finnish (FIN)

AF:

0.366

AC:

3866

AN:

10572

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.370

AC:

25153

AN:

67964

Other (OTH)

AF:

0.357

AC:

751

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1784

3568

5352

7136

8920

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

552

1104

1656

2208

2760

<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:

0.364

Hom.:

41961

Bravo

AF:

0.371

Asia WGS

AF:

0.425

AC:

1480

AN:

3478

EpiCase

AF:

0.365

EpiControl

AF:

0.362

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autosomal dominant popliteal pterygium syndrome (1)

not specified (1)

Orofacial cleft 6, susceptibility to (1)

Van der Woude syndrome 1 (1)

Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.29

(source)

DANN

Benign

0.68

PhyloP100

-1.7

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over