NM_020639.3:c.1884C>T

Variant names:

• chr21-41741309-G-A
• rs55812846
• NM_020639.3:c.1884C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020639.3(RIPK4):​c.1884C>T​(p.Ser628Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,608,500 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 35)
  • Exomes 𝑓: 0.0054 (34 hom.)
• Consequence: RIPK4 NM_020639.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.91
• 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: G2P, Orphanet
• 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 21-41741309-G-A is Benign according to our data. Variant chr21-41741309-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.91 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00474 (722/152298) while in subpopulation NFE AF = 0.00541 (368/68010). AF 95% confidence interval is 0.00496. There are 8 homozygotes in GnomAd4. There are 343 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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.1884C>T	p.Ser628Ser	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.1884C>T	p.Ser628Ser	synonymous	Exon 8 of 8	ENSP00000332454.3	P57078-2
	RIPK4	ENST00000352483.3	TSL:5	c.2028C>T	p.Ser676Ser	synonymous	Exon 9 of 9	ENSP00000330161.2	P57078-1
	ENSG00000236883	ENST00000423276.1	TSL:3	n.*1G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 722 AN: 152180 Hom.: 8 Cov.: 35

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00538 AC: 1310 AN: 243718 AF XY: 0.00546

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00536 AC: 7803 AN: 1456202 Hom.: 34 Cov.: 92 AF XY: 0.00526 AC XY: 3813 AN XY: 724708

African (AFR) AF: 0.000867 AC: 29 AN: 33464

American (AMR) AF: 0.00168 AC: 75 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00989 AC: 258 AN: 26090

East Asian (EAS) AF: 0.00123 AC: 49 AN: 39680

South Asian (SAS) AF: 0.00113 AC: 97 AN: 86210

European-Finnish (FIN) AF: 0.0136 AC: 657 AN: 48302

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5766

European-Non Finnish (NFE) AF: 0.00568 AC: 6310 AN: 1111668

Other (OTH) AF: 0.00444 AC: 268 AN: 60328

GnomAD4 genome AF: 0.00474 AC: 722 AN: 152298 Hom.: 8 Cov.: 35 AF XY: 0.00461 AC XY: 343 AN XY: 74484

African (AFR) AF: 0.00137 AC: 57 AN: 41568

American (AMR) AF: 0.00248 AC: 38 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00541 AC: 368 AN: 68010

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00555 Hom.: 3

Bravo AF: 0.00420

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00545

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Bartsocas-Papas syndrome 1 (1)
-	-	1	not specified (1)
-	-	1	RIPK4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.32
DANN	Benign	0.87
PhyloP100		-4.9
Mutation Taster		=99/1	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: rs55812846; hg19: chr21-43161469; COSMIC: COSV60188551; COSMIC: COSV60188551;