rs861019

Variant names:

• chr1-209802041-A-G
• rs861019
• NM_006147.4:c.-73T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-209802041-A-G
• chr1-209802041-A-C

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.-73T>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 152,032 control chromosomes in the GnomAD database, including 14,711 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14703 hom., cov: 32)
  • Exomes 𝑓: 0.50 (8 hom.)
• Consequence: IRF6 NM_006147.4 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.207
• Publications: 28 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=-0.89).
• BP6: Variant 1-209802041-A-G is Benign according to our data. Variant chr1-209802041-A-G is described in ClinVar as Benign. ClinVar VariationId is 295214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.5 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.-73T>C		splice_region	Exon 2 of 9	NP_006138.1	G0Z349
	IRF6	NM_006147.4	MANE Select	c.-73T>C		5_prime_UTR	Exon 2 of 9	NP_006138.1	G0Z349
	IRF6	NM_001206696.2		c.-112+3906T>C		intron	N/A	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.-73T>C		splice_region	Exon 2 of 9	ENSP00000355988.3	O14896-1
	ENSG00000289700	ENST00000696133.1		c.-73T>C		splice_region	Exon 2 of 10	ENSP00000512426.1	A0A8Q3SJ75
	IRF6	ENST00000367021.8	TSL:1 MANE Select	c.-73T>C		5_prime_UTR	Exon 2 of 9	ENSP00000355988.3	O14896-1

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65741 AN: 151866 Hom.: 14686 Cov.: 32

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.452

GnomAD4 exome AF: 0.500 AC: 24 AN: 48 Hom.: 8 Cov.: 0 AF XY: 0.531 AC XY: 17 AN XY: 32

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) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.475 AC: 19 AN: 40

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.433 AC: 65802 AN: 151984 Hom.: 14703 Cov.: 32 AF XY: 0.427 AC XY: 31678 AN XY: 74272

African (AFR) AF: 0.505 AC: 20939 AN: 41436

American (AMR) AF: 0.329 AC: 5028 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1801 AN: 3470

East Asian (EAS) AF: 0.242 AC: 1248 AN: 5166

South Asian (SAS) AF: 0.350 AC: 1684 AN: 4816

European-Finnish (FIN) AF: 0.393 AC: 4158 AN: 10576

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29429 AN: 67936

Other (OTH) AF: 0.453 AC: 955 AN: 2108

Alfa AF: 0.435 Hom.: 19021

Bravo AF: 0.430

Asia WGS AF: 0.333 AC: 1156 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (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	-0.89
CADD	Benign	1.1
DANN	Benign	0.45
PhyloP100		-0.21
PromoterAI		-0.0038	Neutral
Mutation Taster		=300/0	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: rs861019; hg19: chr1-209975386;