NM_020639.3:c.2331G>A

Variant names:

• chr21-41740862-C-T
• rs7276592
• NM_020639.3:c.2331G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020639.3(RIPK4):​c.2331G>A​(p.Thr777Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 1,608,350 control chromosomes in the GnomAD database, including 157,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14016 hom., cov: 33)
  • Exomes 𝑓: 0.44 (143370 hom.)
• Consequence: RIPK4 NM_020639.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.49
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-41740862-C-T is Benign according to our data. Variant chr21-41740862-C-T is described in ClinVar as Benign. ClinVar VariationId is 261351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020639.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK4	NM_020639.3	MANE Select	c.2331G>A	p.Thr777Thr	synonymous	Exon 8 of 8	NP_065690.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK4	ENST00000332512.8	TSL:1 MANE Select	c.2331G>A	p.Thr777Thr	synonymous	Exon 8 of 8	ENSP00000332454.3
	RIPK4	ENST00000352483.3	TSL:5	c.2475G>A	p.Thr825Thr	synonymous	Exon 9 of 9	ENSP00000330161.2
	ENSG00000236883	ENST00000423276.1	TSL:3	n.300-285C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64272 AN: 151924 Hom.: 14014 Cov.: 33

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.452

GnomAD2 exomes AF: 0.449 AC: 109646 AN: 243950 AF XY: 0.449

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.466

Gnomad ASJ exome AF: 0.429

Gnomad EAS exome AF: 0.604

Gnomad FIN exome AF: 0.478

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.442 AC: 643395 AN: 1456308 Hom.: 143370 Cov.: 61 AF XY: 0.441 AC XY: 319220 AN XY: 724108

African (AFR) AF: 0.316 AC: 10544 AN: 33392

American (AMR) AF: 0.469 AC: 20835 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 11085 AN: 25960

East Asian (EAS) AF: 0.620 AC: 24583 AN: 39630

South Asian (SAS) AF: 0.394 AC: 33869 AN: 85914

European-Finnish (FIN) AF: 0.473 AC: 24267 AN: 51324

Middle Eastern (MID) AF: 0.413 AC: 2293 AN: 5558

European-Non Finnish (NFE) AF: 0.441 AC: 489641 AN: 1109880

Other (OTH) AF: 0.437 AC: 26278 AN: 60180

GnomAD4 genome AF: 0.423 AC: 64296 AN: 152042 Hom.: 14016 Cov.: 33 AF XY: 0.425 AC XY: 31596 AN XY: 74338

African (AFR) AF: 0.320 AC: 13294 AN: 41496

American (AMR) AF: 0.484 AC: 7397 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1514 AN: 3470

East Asian (EAS) AF: 0.608 AC: 3129 AN: 5146

South Asian (SAS) AF: 0.401 AC: 1939 AN: 4830

European-Finnish (FIN) AF: 0.475 AC: 5014 AN: 10554

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.450 AC: 30578 AN: 67946

Other (OTH) AF: 0.453 AC: 955 AN: 2110

Alfa AF: 0.432 Hom.: 4420

Bravo AF: 0.423

Asia WGS AF: 0.470 AC: 1634 AN: 3478

EpiCase AF: 0.452

EpiControl AF: 0.453

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Bartsocas-Papas syndrome 1 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.027
DANN	Benign	0.70
PhyloP100		-3.5
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: rs7276592; hg19: chr21-43161022; COSMIC: COSV60185920;