1-209796405-C-G

Variant names:

• chr1-209796405-C-G
• rs12126910
• NM_006147.4:c.322G>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

The NM_006147.4(IRF6):​c.322G>C​(p.Val108Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.923

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]

ENSG00000289700 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_006147.4
• 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 orofacial cleft 6, susceptibility to, van der Woude syndrome, autosomal dominant popliteal pterygium syndrome, tooth agenesis, van der Woude syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22071412).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.322G>C	p.Val108Leu	missense_variant	Exon 4 of 9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.37G>C	p.Val13Leu	missense_variant	Exon 2 of 7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.322G>C	p.Val108Leu	missense_variant	Exon 4 of 9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.322G>C	p.Val108Leu	missense_variant	Exon 4 of 10			ENSP00000512426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727242

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: 0.0000189

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	.;D;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	-0.20	.;N;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.24	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.24	T;D;T
Sift4G	Benign	0.49	T;T;.
Polyphen		0.0	.;B;.
Vest4		0.11
MutPred		0.60		.;Loss of methylation at K109 (P = 0.0629);Loss of methylation at K109 (P = 0.0629);
MVP		0.68
MPC		1.2
ClinPred		0.66	D
GERP RS		5.6
Varity_R		0.21
gMVP		0.36

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: rs12126910; hg19: chr1-209969750;