1-209788625-C-G

Variant names:

• chr1-209788625-C-G
• rs200166664
• NM_006147.4:c.1199G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM5 PP2 PP3 BP4_Strong

The NM_006147.4(IRF6):​c.1199G>C​(p.Arg400Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R400Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.32
• Publications: 11 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 0 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-209788625-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 101515.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.
• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009464204).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	NM_006147.4	MANE Select	c.1199G>C	p.Arg400Pro	missense	Exon 9 of 9	NP_006138.1
	IRF6	NM_001206696.2		c.914G>C	p.Arg305Pro	missense	Exon 7 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.1199G>C	p.Arg400Pro	missense	Exon 9 of 9	ENSP00000355988.3
	ENSG00000289700	ENST00000696133.1		c.1199G>C	p.Arg400Pro	missense	Exon 9 of 10	ENSP00000512426.1
	IRF6	ENST00000542854.5	TSL:2	c.914G>C	p.Arg305Pro	missense	Exon 7 of 7	ENSP00000440532.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0286 AC: 5601 AN: 195770 AF XY: 0.0287

Gnomad AFR exome AF: 0.0552

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.00701

Gnomad EAS exome AF: 0.0471

Gnomad FIN exome AF: 0.0409

Gnomad NFE exome AF: 0.0273

Gnomad OTH exome AF: 0.0132

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00316 AC: 4519 AN: 1429524 Hom.: 5 Cov.: 31 AF XY: 0.00348 AC XY: 2465 AN XY: 708976

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00917 AC: 297 AN: 32390

American (AMR) AF: 0.0282 AC: 1109 AN: 39316

Ashkenazi Jewish (ASJ) AF: 0.00183 AC: 46 AN: 25146

East Asian (EAS) AF: 0.0177 AC: 662 AN: 37422

South Asian (SAS) AF: 0.00338 AC: 279 AN: 82664

European-Finnish (FIN) AF: 0.0102 AC: 486 AN: 47640

Middle Eastern (MID) AF: 0.00109 AC: 6 AN: 5524

European-Non Finnish (NFE) AF: 0.00138 AC: 1513 AN: 1100074

Other (OTH) AF: 0.00204 AC: 121 AN: 59348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152010 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74228

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000561 Hom.: 0

ExAC AF: 0.0446 AC: 5310

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0095	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.49
MPC		2.0
ClinPred		0.057	T
GERP RS		5.7
Varity_R		0.98
gMVP		0.95
Mutation Taster		=3/97	disease causing

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: rs200166664; hg19: chr1-209961970; COSMIC: COSV54213301; COSMIC: COSV54213301;