21-41741092-G-T

Position:

• chr21-41741092-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020639.3(RIPK4):​c.2101C>A​(p.Pro701Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,848 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RIPK4 NM_020639.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.89

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26611835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPK4	NM_020639.3	c.2101C>A	p.Pro701Thr	missense_variant	8/8	ENST00000332512.8	NP_065690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPK4	ENST00000332512.8	c.2101C>A	p.Pro701Thr	missense_variant	8/8	1	NM_020639.3	ENSP00000332454	P1
	ENST00000423276.1	n.300-55G>T		intron_variant, non_coding_transcript_variant		3
RIPK4	ENST00000352483.3	c.2245C>A	p.Pro749Thr	missense_variant	9/9	5		ENSP00000330161

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459848 Hom.: 0 Cov.: 84 AF XY: 0.00000138 AC XY: 1 AN XY: 726288

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.87	L;.
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.18
Sift	Benign	0.16	T;T
Sift4G	Benign	0.49	T;T
Polyphen		1.0	.;D
Vest4		0.17
MutPred		0.28		.;Gain of phosphorylation at P701 (P = 0.1009);
MVP		0.75
MPC		1.4
ClinPred		0.82	D
GERP RS		4.6
Varity_R		0.093
gMVP		0.30

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: rs35537517; hg19: chr21-43161252; COSMIC: COSV60189064;