rs599021

Variant names:

• chr1-209787577-A-C
• rs599021
• NM_006147.4:c.*843T>G

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.*843T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 152,048 control chromosomes in the GnomAD database, including 10,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10687 hom., cov: 31)
  • Exomes 𝑓: 0.32 (10 hom.)
• Consequence: IRF6 NM_006147.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.266
• Publications: 15 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=-0.79).
• BP6: Variant 1-209787577-A-C is Benign according to our data. Variant chr1-209787577-A-C is described in ClinVar as Benign. ClinVar VariationId is 295189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.429 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.*843T>G		3_prime_UTR	Exon 9 of 9	NP_006138.1	G0Z349
	IRF6	NM_001206696.2		c.*843T>G		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.*843T>G		3_prime_UTR	Exon 9 of 9	ENSP00000355988.3	O14896-1
	ENSG00000289700	ENST00000696133.1		c.1400+847T>G		intron	N/A	ENSP00000512426.1	A0A8Q3SJ75
	IRF6	ENST00000863915.1		c.*843T>G		3_prime_UTR	Exon 8 of 8	ENSP00000533974.1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55075 AN: 151750 Hom.: 10686 Cov.: 31

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.322 AC: 58 AN: 180 Hom.: 10 Cov.: 0 AF XY: 0.329 AC XY: 46 AN XY: 140

African (AFR) AF: 0.417 AC: 5 AN: 12

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.125 AC: 1 AN: 8

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.227 AC: 5 AN: 22

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.393 AC: 44 AN: 112

Other (OTH) AF: 0.136 AC: 3 AN: 22

GnomAD4 genome AF: 0.363 AC: 55098 AN: 151868 Hom.: 10687 Cov.: 31 AF XY: 0.359 AC XY: 26647 AN XY: 74206

African (AFR) AF: 0.261 AC: 10801 AN: 41396

American (AMR) AF: 0.301 AC: 4592 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1803 AN: 3466

East Asian (EAS) AF: 0.242 AC: 1247 AN: 5154

South Asian (SAS) AF: 0.353 AC: 1697 AN: 4806

European-Finnish (FIN) AF: 0.394 AC: 4155 AN: 10550

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29391 AN: 67930

Other (OTH) AF: 0.408 AC: 857 AN: 2098

Alfa AF: 0.392 Hom.: 3648

Bravo AF: 0.349

Asia WGS AF: 0.318 AC: 1104 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	-0.79
CADD	Benign	4.1
DANN	Benign	0.64
PhyloP100		0.27
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: rs599021; hg19: chr1-209960922;