rs680331

Variant names:

• chr1-209786527-G-A
• rs680331
• NM_006147.4:c.*1893C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006147.4(IRF6):​c.*1893C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 152,042 control chromosomes in the GnomAD database, including 49,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49784 hom., cov: 30)
  • Exomes 𝑓: 0.75 (3 hom.)
• Consequence: IRF6 NM_006147.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0200
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-209786527-G-A is Benign according to our data. Variant chr1-209786527-G-A is described in ClinVar as Benign. ClinVar VariationId is 295178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

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.*1893C>T		3_prime_UTR	Exon 9 of 9	NP_006138.1	G0Z349
	IRF6	NM_001206696.2		c.*1893C>T		3_prime_UTR	Exon 7 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.*1893C>T		3_prime_UTR	Exon 9 of 9	ENSP00000355988.3	O14896-1
	ENSG00000289700	ENST00000696133.1		c.1400+1897C>T		intron	N/A	ENSP00000512426.1	A0A8Q3SJ75
	IRF6	ENST00000863915.1		c.*1893C>T		3_prime_UTR	Exon 8 of 8	ENSP00000533974.1

Frequencies

GnomAD3 genomes AF: 0.809 AC: 122861 AN: 151916 Hom.: 49753 Cov.: 30

Gnomad AFR AF: 0.847

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.827

Gnomad ASJ AF: 0.829

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.792

Gnomad OTH AF: 0.819

GnomAD4 exome AF: 0.750 AC: 6 AN: 8 Hom.: 3 Cov.: 0 AF XY: 0.667 AC XY: 4 AN XY: 6

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.667 AC: 4 AN: 6

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.809 AC: 122947 AN: 152034 Hom.: 49784 Cov.: 30 AF XY: 0.806 AC XY: 59898 AN XY: 74306

African (AFR) AF: 0.847 AC: 35126 AN: 41466

American (AMR) AF: 0.826 AC: 12632 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.829 AC: 2878 AN: 3472

East Asian (EAS) AF: 0.806 AC: 4166 AN: 5168

South Asian (SAS) AF: 0.780 AC: 3755 AN: 4816

European-Finnish (FIN) AF: 0.742 AC: 7825 AN: 10542

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.792 AC: 53821 AN: 67980

Other (OTH) AF: 0.816 AC: 1717 AN: 2104

Alfa AF: 0.813 Hom.: 39798

Bravo AF: 0.814

Asia WGS AF: 0.756 AC: 2632 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Orofacial cleft 6, susceptibility to (1)
-	-	1	Van der Woude syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.0
DANN	Benign	0.64
PhyloP100		-0.020
Mutation Taster		=100/0	polymorphism (auto)

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: rs680331; hg19: chr1-209959872;