chr1-209796557-G-C

Variant names:

• chr1-209796557-G-C
• rs7552506
• NM_006147.4:c.175-5C>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.175-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,609,454 control chromosomes in the GnomAD database, including 98,133 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7900 hom., cov: 31)
  • Exomes 𝑓: 0.35 (90233 hom.)
• Consequence: IRF6 NM_006147.4 splice_region, intron
• Scores: Splicing: ADA: 0.002065
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.33
• Publications: 27 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=-0.82).
• BP6: Variant 1-209796557-G-C is Benign according to our data. Variant chr1-209796557-G-C is described in ClinVar as Benign. ClinVar VariationId is 259923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.353 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.175-5C>G		splice_region intron	N/A	NP_006138.1	G0Z349
	IRF6	NM_001206696.2		c.-111-5C>G		splice_region 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.175-5C>G		splice_region intron	N/A	ENSP00000355988.3	O14896-1
	ENSG00000289700	ENST00000696133.1		c.175-5C>G		splice_region intron	N/A	ENSP00000512426.1	A0A8Q3SJ75
	IRF6	ENST00000863915.1		c.175-5C>G		splice_region intron	N/A	ENSP00000533974.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48465 AN: 151492 Hom.: 7901 Cov.: 31

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.321

GnomAD2 exomes AF: 0.322 AC: 80731 AN: 250510 AF XY: 0.324

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.290

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.349 AC: 508331 AN: 1457842 Hom.: 90233 Cov.: 35 AF XY: 0.348 AC XY: 252696 AN XY: 725332

African (AFR) AF: 0.271 AC: 9050 AN: 33400

American (AMR) AF: 0.299 AC: 13365 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7549 AN: 26110

East Asian (EAS) AF: 0.152 AC: 6032 AN: 39670

South Asian (SAS) AF: 0.330 AC: 28450 AN: 86114

European-Finnish (FIN) AF: 0.365 AC: 19441 AN: 53262

Middle Eastern (MID) AF: 0.303 AC: 1347 AN: 4446

European-Non Finnish (NFE) AF: 0.363 AC: 403226 AN: 1110014

Other (OTH) AF: 0.330 AC: 19871 AN: 60152

GnomAD4 genome AF: 0.320 AC: 48477 AN: 151612 Hom.: 7900 Cov.: 31 AF XY: 0.317 AC XY: 23510 AN XY: 74092

African (AFR) AF: 0.272 AC: 11215 AN: 41282

American (AMR) AF: 0.313 AC: 4772 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1058 AN: 3470

East Asian (EAS) AF: 0.155 AC: 798 AN: 5142

South Asian (SAS) AF: 0.335 AC: 1609 AN: 4806

European-Finnish (FIN) AF: 0.353 AC: 3697 AN: 10464

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24228 AN: 67902

Other (OTH) AF: 0.317 AC: 665 AN: 2098

Alfa AF: 0.333 Hom.: 2713

Bravo AF: 0.313

Asia WGS AF: 0.234 AC: 817 AN: 3478

EpiCase AF: 0.353

EpiControl AF: 0.349

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant popliteal pterygium syndrome (1)
-	-	1	not specified (1)
-	-	1	Van der Woude syndrome 1 (1)
-	-	1	Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		1.3
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
dbscSNV1_RF	Benign	0.074
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: rs7552506; hg19: chr1-209969902; COSMIC: COSV65419346; COSMIC: COSV65419346;