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: Orphanet, G2P
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK4	NM_020639.3	c.1476G>A	p.Ala492Ala	synonymous_variant	Exon 8 of 8	ENST00000332512.8	NP_065690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK4	ENST00000332512.8	c.1476G>A	p.Ala492Ala	synonymous_variant	Exon 8 of 8	1	NM_020639.3	ENSP00000332454.3
RIPK4	ENST00000352483.3	c.1620G>A	p.Ala540Ala	synonymous_variant	Exon 9 of 9	5		ENSP00000330161.2

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bartsocas-Papas syndrome 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;