1-209789693-A-T

Variant names:

• chr1-209789693-A-T
• rs61099902
• NM_006147.4:c.1153T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000367021.8(IRF6):​c.1153T>A​(p.Leu385Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L385L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IRF6 ENST00000367021.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.438
• Publications: 3 publications found

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)

ENSG00000289700 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the IRF6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.7435 (below the threshold of 3.09). Trascript score misZ: 3.8897 (above the threshold of 3.09). GenCC associations: The gene is linked to van der Woude syndrome 1, van der Woude syndrome, autosomal dominant popliteal pterygium syndrome, orofacial cleft 6, susceptibility to, tooth agenesis, IRF6-related condition, popliteal pterygium syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11144507).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367021.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	NM_006147.4	MANE Select	c.1153T>A	p.Leu385Met	missense	Exon 8 of 9	NP_006138.1
	IRF6	NM_001206696.2		c.868T>A	p.Leu290Met	missense	Exon 6 of 7	NP_001193625.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	ENST00000367021.8	TSL:1 MANE Select	c.1153T>A	p.Leu385Met	missense	Exon 8 of 9	ENSP00000355988.3
	ENSG00000289700	ENST00000696133.1		c.1153T>A	p.Leu385Met	missense	Exon 8 of 10	ENSP00000512426.1
	IRF6	ENST00000542854.5	TSL:2	c.868T>A	p.Leu290Met	missense	Exon 6 of 7	ENSP00000440532.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461264 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727000

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111476

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.00098	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.44
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.28	B
Vest4		0.27
MutPred		0.38		Gain of disorder (P = 0.1095)
MVP		0.42
MPC		0.84
ClinPred		0.41	T
GERP RS		0.31
Varity_R		0.18
gMVP		0.23
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs61099902; hg19: chr1-209963038;