NM_020639.3:c.1005G>T

Variant names:

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

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 CliVar as Benign. Clinvar id is 261346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-41744072-C-A is described in CliVar as Benign. Clinvar id is 261346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-41744072-C-A is described in CliVar as Benign. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK4	NM_020639.3	c.1005G>T	p.Leu335Leu	synonymous_variant	Exon 7 of 8	ENST00000332512.8	NP_065690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK4	ENST00000332512.8	c.1005G>T	p.Leu335Leu	synonymous_variant	Exon 7 of 8	1	NM_020639.3	ENSP00000332454.3
RIPK4	ENST00000352483.3	c.1149G>T	p.Leu383Leu	synonymous_variant	Exon 8 of 9	5		ENSP00000330161.2

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bartsocas-Papas syndrome 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs2277789; hg19: chr21-43164232; COSMIC: COSV60186015; COSMIC: COSV60186015;