rs1553248247

Variant names:

• chr1-209796365-C-A
• rs1553248247
• NM_006147.4:c.362G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BP6

The NM_006147.4(IRF6):​c.362G>T​(p.Gly121Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.25
• Publications: 0 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, Labcorp Genetics (formerly Invitae), G2P
• IRF6-related condition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• van der Woude syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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=0.362893).
• BP6: Variant 1-209796365-C-A is Benign according to our data. Variant chr1-209796365-C-A is described in ClinVar as Benign. ClinVar VariationId is 559488.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006147.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	NM_006147.4	MANE Select	c.362G>T	p.Gly121Val	missense	Exon 4 of 9	NP_006138.1	G0Z349
	IRF6	NM_001206696.2		c.77G>T	p.Gly26Val	missense	Exon 2 of 7	NP_001193625.1	O14896-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	ENST00000367021.8	TSL:1 MANE Select	c.362G>T	p.Gly121Val	missense	Exon 4 of 9	ENSP00000355988.3	O14896-1
	ENSG00000289700	ENST00000696133.1		c.362G>T	p.Gly121Val	missense	Exon 4 of 10	ENSP00000512426.1	A0A8Q3SJ75
	IRF6	ENST00000863915.1		c.362G>T	p.Gly121Val	missense	Exon 3 of 8	ENSP00000533974.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Orofacial cleft 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.082	T
Polyphen		0.030	B
Vest4		0.58
MutPred		0.34		Gain of catalytic residue at G121 (P = 0.0078)
MVP		0.75
MPC		1.5
ClinPred		0.68	D
GERP RS		5.6
Varity_R		0.25
gMVP		0.55
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1553248247; hg19: chr1-209969710;