21-41741990-G-A

Variant names:

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

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.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
• Publications: 19 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: G2P, Orphanet
• ectodermal dysplasia syndrome

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK4	NM_020639.3	MANE Select	c.1203C>T	p.Gly401Gly	synonymous	Exon 8 of 8	NP_065690.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK4	ENST00000332512.8	TSL:1 MANE Select	c.1203C>T	p.Gly401Gly	synonymous	Exon 8 of 8	ENSP00000332454.3	P57078-2
	RIPK4	ENST00000352483.3	TSL:5	c.1347C>T	p.Gly449Gly	synonymous	Exon 9 of 9	ENSP00000330161.2	P57078-1

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

GnomAD2 exomes AF: 0.450 AC: 104023 AN: 230908 AF XY: 0.451

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 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

African (AFR) AF: 0.316 AC: 10417 AN: 32962

American (AMR) AF: 0.469 AC: 20349 AN: 43414

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 9920 AN: 24356

East Asian (EAS) AF: 0.607 AC: 23896 AN: 39358

South Asian (SAS) AF: 0.392 AC: 32190 AN: 82104

European-Finnish (FIN) AF: 0.472 AC: 24429 AN: 51714

Middle Eastern (MID) AF: 0.406 AC: 2295 AN: 5654

European-Non Finnish (NFE) AF: 0.441 AC: 483692 AN: 1096090

Other (OTH) AF: 0.435 AC: 25761 AN: 59194

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

African (AFR) AF: 0.320 AC: 13295 AN: 41484

American (AMR) AF: 0.484 AC: 7401 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1452 AN: 3470

East Asian (EAS) AF: 0.597 AC: 3070 AN: 5146

South Asian (SAS) AF: 0.398 AC: 1920 AN: 4820

European-Finnish (FIN) AF: 0.475 AC: 5028 AN: 10584

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30574 AN: 67952

Other (OTH) AF: 0.454 AC: 958 AN: 2110

Alfa AF: 0.440 Hom.: 58734

Bravo AF: 0.422

Asia WGS AF: 0.464 AC: 1613 AN: 3478

ClinVar

ClinVar submissions

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	-0.64
CADD	Benign	7.5
DANN	Benign	0.88
PhyloP100		1.0
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: rs3746894; hg19: chr21-43162150; COSMIC: COSV60185526; COSMIC: COSV60185526;