rs3746894

Variant names:

• chr21-41741990-G-A
• rs3746894
• NM_020639.3:c.1203C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-41741990-G-A
• chr21-41741990-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020639.3(RIPK4):​c.1203C>T​(p.Gly401Gly) 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 1,586,898 control chromosomes in the GnomAD database, including 154,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13939 hom., cov: 33)
  • Exomes 𝑓: 0.44 (140806 hom.)
• Consequence: RIPK4 NM_020639.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.02

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 21-41741990-G-A is Benign according to our data. Variant chr21-41741990-G-A is described in ClinVar as [Benign]. Clinvar id is 261347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.02 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.1203C>T	p.Gly401Gly	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.1203C>T	p.Gly401Gly	synonymous_variant	Exon 8 of 8	1	NM_020639.3	ENSP00000332454.3
RIPK4	ENST00000352483.3	c.1347C>T	p.Gly449Gly	synonymous_variant	Exon 9 of 9	5		ENSP00000330161.2

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64154 AN: 151934 Hom.: 13936 Cov.: 33

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.596

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.453

GnomAD3 exomes AF: 0.450 AC: 104023 AN: 230908 Hom.: 23954 AF XY: 0.451 AC XY: 56188 AN XY: 124518

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.417

Gnomad EAS exome AF: 0.592

Gnomad SAS exome AF: 0.398

Gnomad FIN exome AF: 0.478

Gnomad NFE exome AF: 0.450

Gnomad OTH exome AF: 0.460

GnomAD4 exome AF: 0.441 AC: 632949 AN: 1434846 Hom.: 140806 Cov.: 42 AF XY: 0.440 AC XY: 312643 AN XY: 710038

Gnomad4 AFR exome AF: 0.316

Gnomad4 AMR exome AF: 0.469

Gnomad4 ASJ exome AF: 0.407

Gnomad4 EAS exome AF: 0.607

Gnomad4 SAS exome AF: 0.392

Gnomad4 FIN exome AF: 0.472

Gnomad4 NFE exome AF: 0.441

Gnomad4 OTH exome AF: 0.435

GnomAD4 genome AF: 0.422 AC: 64179 AN: 152052 Hom.: 13939 Cov.: 33 AF XY: 0.424 AC XY: 31538 AN XY: 74336

Gnomad4 AFR AF: 0.320

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.597

Gnomad4 SAS AF: 0.398

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.454

Alfa AF: 0.447 Hom.: 29186

Bravo AF: 0.422

Asia WGS AF: 0.464 AC: 1613 AN: 3478

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	-0.64
CADD	Benign	7.5
DANN	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs3746894; hg19: chr21-43162150; COSMIC: COSV60185526; COSMIC: COSV60185526;