1-209789693-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006147.4(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. 14/21 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 NM_006147.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.438

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, IRF6
• BP4: Computational evidence support a benign effect (MetaRNN=0.11144507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4	c.1153T>A	p.Leu385Met	missense_variant	8/9	ENST00000367021.8
IRF6	NM_001206696.2	c.868T>A	p.Leu290Met	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.1153T>A	p.Leu385Met	missense_variant	8/9	1	NM_006147.4	P1
IRF6	ENST00000542854.5	c.868T>A	p.Leu290Met	missense_variant	6/7	2
IRF6	ENST00000643798.1	c.*663T>A		3_prime_UTR_variant, NMD_transcript_variant	8/9
IRF6	ENST00000696134.1	c.*580T>A		3_prime_UTR_variant, NMD_transcript_variant	8/9

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

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.38	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0060	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs61099902; hg19: chr1-209963038;