rs3746893

Variant names:

• chr21-41741717-C-T
• rs3746893
• NM_020639.3:c.1476G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020639.3(RIPK4):​c.1476G>A​(p.Ala492Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,613,042 control chromosomes in the GnomAD database, including 157,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13957 hom., cov: 33)
  • Exomes 𝑓: 0.44 (143098 hom.)
• Consequence: RIPK4 NM_020639.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.760
• Publications: 20 publications found

Genes affected

RIPK4 (HGNC:496): (receptor interacting serine/threonine kinase 4) The protein encoded by this gene is a serine/threonine protein kinase that interacts with protein kinase C-delta. The encoded protein can also activate NFkappaB and is required for keratinocyte differentiation. This kinase undergoes autophosphorylation. [provided by RefSeq, Jul 2008]

RIPK4 Gene-Disease associations (from GenCC):

• Bartsocas-Papas syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• ectodermal dysplasia syndrome

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 21-41741717-C-T is Benign according to our data. Variant chr21-41741717-C-T is described in ClinVar as Benign. ClinVar VariationId is 261348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020639.3. 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
	RIPK4	NM_020639.3	MANE Select	c.1476G>A	p.Ala492Ala	synonymous	Exon 8 of 8	NP_065690.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK4	ENST00000332512.8	TSL:1 MANE Select	c.1476G>A	p.Ala492Ala	synonymous	Exon 8 of 8	ENSP00000332454.3	P57078-2
	RIPK4	ENST00000352483.3	TSL:5	c.1620G>A	p.Ala540Ala	synonymous	Exon 9 of 9	ENSP00000330161.2	P57078-1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64220 AN: 151974 Hom.: 13955 Cov.: 33

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.453

GnomAD2 exomes AF: 0.447 AC: 112125 AN: 250754 AF XY: 0.447

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.465

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.590

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.448

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.441 AC: 644043 AN: 1460950 Hom.: 143098 Cov.: 88 AF XY: 0.440 AC XY: 319718 AN XY: 726852

African (AFR) AF: 0.316 AC: 10594 AN: 33480

American (AMR) AF: 0.468 AC: 20922 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 10612 AN: 26134

East Asian (EAS) AF: 0.607 AC: 24086 AN: 39698

South Asian (SAS) AF: 0.392 AC: 33818 AN: 86258

European-Finnish (FIN) AF: 0.472 AC: 24802 AN: 52504

Middle Eastern (MID) AF: 0.406 AC: 2344 AN: 5768

European-Non Finnish (NFE) AF: 0.441 AC: 490616 AN: 1111996

Other (OTH) AF: 0.435 AC: 26249 AN: 60388

GnomAD4 genome AF: 0.422 AC: 64246 AN: 152092 Hom.: 13957 Cov.: 33 AF XY: 0.425 AC XY: 31580 AN XY: 74364

African (AFR) AF: 0.321 AC: 13332 AN: 41480

American (AMR) AF: 0.484 AC: 7403 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1452 AN: 3472

East Asian (EAS) AF: 0.597 AC: 3089 AN: 5174

South Asian (SAS) AF: 0.400 AC: 1928 AN: 4824

European-Finnish (FIN) AF: 0.475 AC: 5021 AN: 10568

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30583 AN: 67970

Other (OTH) AF: 0.454 AC: 959 AN: 2112

Alfa AF: 0.438 Hom.: 34228

Bravo AF: 0.422

Asia WGS AF: 0.464 AC: 1613 AN: 3478

EpiCase AF: 0.451

EpiControl AF: 0.453

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Bartsocas-Papas syndrome 1 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.2
DANN	Benign	0.89
PhyloP100		-0.76
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: rs3746893; hg19: chr21-43161877; COSMIC: COSV60185720; COSMIC: COSV60185720;