rs13050509

Variant names:

• chr21-41740097-C-T
• rs13050509
• NM_020639.3:c.*741G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_020639.3(RIPK4):​c.*741G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 152,128 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RIPK4 NM_020639.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.31
• Publications: 4 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

ENSG00000236883 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0184 (2803/152128) while in subpopulation SAS AF = 0.0411 (198/4814). AF 95% confidence interval is 0.0364. There are 40 homozygotes in GnomAd4. There are 1373 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK4	NM_020639.3	c.*741G>A		3_prime_UTR_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.*741G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_020639.3	ENSP00000332454.3
RIPK4	ENST00000352483.3	c.*741G>A		3_prime_UTR_variant	Exon 9 of 9	5		ENSP00000330161.2
ENSG00000236883	ENST00000423276.1	n.299+426C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2804 AN: 152010 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0411

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0273

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0184 AC: 2803 AN: 152128 Hom.: 40 Cov.: 33 AF XY: 0.0185 AC XY: 1373 AN XY: 74368

African (AFR) AF: 0.00349 AC: 145 AN: 41492

American (AMR) AF: 0.0209 AC: 319 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.0411 AC: 198 AN: 4814

European-Finnish (FIN) AF: 0.0216 AC: 229 AN: 10588

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0244 AC: 1657 AN: 68018

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0215 Hom.: 30

Bravo AF: 0.0171

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bartsocas-Papas syndrome 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.12
DANN	Benign	0.61
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

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: rs13050509; hg19: chr21-43160257;