chr21-41754276-A-C

Variant names:

• chr21-41754276-A-C
• rs6586235
• NM_020639.3:c.474+2249T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020639.3(RIPK4):​c.474+2249T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 152,052 control chromosomes in the GnomAD database, including 22,200 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 0.54 (22200 hom., cov: 33)
• Consequence: RIPK4 NM_020639.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK4	NM_020639.3	c.474+2249T>G		intron_variant	Intron 2 of 7	ENST00000332512.8	NP_065690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK4	ENST00000332512.8	c.474+2249T>G		intron_variant	Intron 2 of 7	1	NM_020639.3	ENSP00000332454.3
RIPK4	ENST00000352483.3	c.474+2249T>G		intron_variant	Intron 2 of 8	5		ENSP00000330161.2

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81647 AN: 151934 Hom.: 22183 Cov.: 33

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.547

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.537 AC: 81709 AN: 152052 Hom.: 22200 Cov.: 33 AF XY: 0.534 AC XY: 39677 AN XY: 74318

African (AFR) AF: 0.562 AC: 23289 AN: 41456

American (AMR) AF: 0.571 AC: 8722 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2093 AN: 3472

East Asian (EAS) AF: 0.331 AC: 1715 AN: 5186

South Asian (SAS) AF: 0.546 AC: 2630 AN: 4818

European-Finnish (FIN) AF: 0.454 AC: 4795 AN: 10562

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36535 AN: 67970

Other (OTH) AF: 0.545 AC: 1149 AN: 2110

Alfa AF: 0.542 Hom.: 37019

Bravo AF: 0.549

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.48
DANN	Benign	0.36
PhyloP100		-1.3
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: rs6586235; hg19: chr21-43174436;