1-209796557-G-C

Position:

chr1-209796557-G-C

Variant summary

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

The NM_006147.4(IRF6):c.175-5C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,609,454 control chromosomes in the GnomAD database, including 98,133 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 7900 hom., cov: 31)

Exomes 𝑓: 0.35 ( 90233 hom. )

Consequence

IRF6
NM_006147.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.002065

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.33

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:

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=-0.82).

BP6

Variant 1-209796557-G-C is Benign according to our data. Variant chr1-209796557-G-C is described in ClinVar as [Benign]. Clinvar id is 259923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-209796557-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4 linkuse as main transcript	c.175-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000367021.8
IRF6	NM_001206696.2 linkuse as main transcript	c.-111-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8 linkuse as main transcript	c.175-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006147.4	P1	O14896-1

Frequencies

GnomAD3 genomes

AF:

0.320

AC:

48465

AN:

151492

Hom.:

7901

Cov.:

show subpopulations

Gnomad AFR

AF:

0.272

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.313

Gnomad ASJ

AF:

0.305

Gnomad EAS

AF:

0.156

Gnomad SAS

AF:

0.334

Gnomad FIN

AF:

0.353

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.357

Gnomad OTH

AF:

0.321

GnomAD3 exomes

AF:

0.322

AC:

80731

AN:

250510

Hom.:

13527

AF XY:

0.324

AC XY:

43846

AN XY:

135430

show subpopulations

Gnomad AFR exome

AF:

0.267

Gnomad AMR exome

AF:

0.298

Gnomad ASJ exome

AF:

0.290

Gnomad EAS exome

AF:

0.154

Gnomad SAS exome

AF:

0.332

Gnomad FIN exome

AF:

0.359

Gnomad NFE exome

AF:

0.358

Gnomad OTH exome

AF:

0.315

GnomAD4 exome

AF:

0.349

AC:

508331

AN:

1457842

Hom.:

90233

Cov.:

AF XY:

0.348

AC XY:

252696

AN XY:

725332

show subpopulations

Gnomad4 AFR exome

AF:

0.271

Gnomad4 AMR exome

AF:

0.299

Gnomad4 ASJ exome

AF:

0.289

Gnomad4 EAS exome

AF:

0.152

Gnomad4 SAS exome

AF:

0.330

Gnomad4 FIN exome

AF:

0.365

Gnomad4 NFE exome

AF:

0.363

Gnomad4 OTH exome

AF:

0.330

GnomAD4 genome

AF:

0.320

AC:

48477

AN:

151612

Hom.:

7900

Cov.:

AF XY:

0.317

AC XY:

23510

AN XY:

74092

show subpopulations

Gnomad4 AFR

AF:

0.272

Gnomad4 AMR

AF:

0.313

Gnomad4 ASJ

AF:

0.305

Gnomad4 EAS

AF:

0.155

Gnomad4 SAS

AF:

0.335

Gnomad4 FIN

AF:

0.353

Gnomad4 NFE

AF:

0.357

Gnomad4 OTH

AF:

0.317

Alfa

AF:

0.333

Hom.:

2713

Bravo

AF:

0.313

Asia WGS

AF:

0.234

AC:

817

AN:

3478

EpiCase

AF:

0.353

EpiControl

AF:

0.349

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Autosomal dominant popliteal pterygium syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Van der Woude syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0021

dbscSNV1_RF

Benign

0.074

SpliceAI score (max)

0.020

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