Variant 1-209789669-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP3PP5

The NM_006147.4(IRF6):c.1177C>T(p.Gln393Ter) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IRF6
NM_006147.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.9981

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.11

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 1-209789669-G-A is Pathogenic according to our data. Variant chr1-209789669-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3413.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF6	NM_006147.4 linkuse as main transcript	c.1177C>T	p.Gln393Ter	stop_gained, splice_region_variant	8/9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2 linkuse as main transcript	c.892C>T	p.Gln298Ter	stop_gained, splice_region_variant	6/7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8 linkuse as main transcript	c.1177C>T	p.Gln393Ter	stop_gained, splice_region_variant	8/9	1	NM_006147.4	ENSP00000355988	P1	O14896-1
IRF6	ENST00000542854.5 linkuse as main transcript	c.892C>T	p.Gln298Ter	stop_gained, splice_region_variant	6/7	2		ENSP00000440532		O14896-2
IRF6	ENST00000643798.1 linkuse as main transcript	c.*687C>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	8/9			ENSP00000496669
IRF6	ENST00000696134.1 linkuse as main transcript	c.*604C>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	8/9			ENSP00000512427

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453032

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723528

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Popliteal pterygium syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.3

Eigen_PC

Pathogenic

1.2

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

A;A

Vest4

0.94

GERP RS

6.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

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