rs2277789

Variant names:

• chr21-41744072-C-A
• rs2277789
• NM_020639.3:c.1005G>T
• RIPK4 p.Leu335Leu

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020639.3(RIPK4):​c.1005G>T​(p.Leu335Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,610,980 control chromosomes in the GnomAD database, including 135,114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11485 hom., cov: 32)
  • Exomes 𝑓: 0.41 (123629 hom.)
• Consequence: RIPK4 NM_020639.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.13
• Publications: 13 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 21-41744072-C-A is Benign according to our data. Variant chr21-41744072-C-A is described in ClinVar as Benign. ClinVar VariationId is 261346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.488 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.1005G>T	p.Leu335Leu	synonymous	Exon 7 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.1005G>T	p.Leu335Leu	synonymous	Exon 7 of 8	ENSP00000332454.3	P57078-2
	RIPK4	ENST00000352483.3	TSL:5	c.1149G>T	p.Leu383Leu	synonymous	Exon 8 of 9	ENSP00000330161.2	P57078-1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58042 AN: 151854 Hom.: 11485 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.404

GnomAD2 exomes AF: 0.403 AC: 99572 AN: 246868 AF XY: 0.402

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.419

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.506

Gnomad FIN exome AF: 0.419

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.410 AC: 598276 AN: 1459008 Hom.: 123629 Cov.: 49 AF XY: 0.408 AC XY: 296033 AN XY: 725580

African (AFR) AF: 0.266 AC: 8888 AN: 33462

American (AMR) AF: 0.424 AC: 18844 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 9382 AN: 26090

East Asian (EAS) AF: 0.504 AC: 19986 AN: 39638

South Asian (SAS) AF: 0.318 AC: 27382 AN: 86134

European-Finnish (FIN) AF: 0.418 AC: 21946 AN: 52444

Middle Eastern (MID) AF: 0.337 AC: 1908 AN: 5666

European-Non Finnish (NFE) AF: 0.419 AC: 465960 AN: 1110876

Other (OTH) AF: 0.398 AC: 23980 AN: 60258

GnomAD4 genome AF: 0.382 AC: 58066 AN: 151972 Hom.: 11485 Cov.: 32 AF XY: 0.383 AC XY: 28463 AN XY: 74288

African (AFR) AF: 0.271 AC: 11240 AN: 41450

American (AMR) AF: 0.443 AC: 6769 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1275 AN: 3466

East Asian (EAS) AF: 0.504 AC: 2591 AN: 5136

South Asian (SAS) AF: 0.335 AC: 1606 AN: 4800

European-Finnish (FIN) AF: 0.412 AC: 4360 AN: 10584

Middle Eastern (MID) AF: 0.366 AC: 107 AN: 292

European-Non Finnish (NFE) AF: 0.426 AC: 28929 AN: 67946

Other (OTH) AF: 0.405 AC: 856 AN: 2114

Alfa AF: 0.396 Hom.: 7239

Bravo AF: 0.383

Asia WGS AF: 0.389 AC: 1349 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	-0.35
CADD	Benign	6.8
DANN	Benign	0.75
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2277789;

hg19: chr21-43164232;

COSMIC: COSV60186015;

COSMIC: COSV60186015;