rs3746891

Variant names:

• chr21-41741197-T-C
• rs3746891
• NM_020639.3:c.1996A>G

Your query was ambiguous. Multiple possible variants found:

• chr21-41741197-T-C
• chr21-41741197-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020639.3(RIPK4):​c.1996A>G​(p.Met666Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.969 in 1,610,228 control chromosomes in the GnomAD database, including 755,817 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72936 hom., cov: 36)
  • Exomes 𝑓: 0.97 (682881 hom.)
• Consequence: RIPK4 NM_020639.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.675
• Publications: 28 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.0242087E-7).
• BP6: Variant 21-41741197-T-C is Benign according to our data. Variant chr21-41741197-T-C is described in ClinVar as Benign. ClinVar VariationId is 261350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.987 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.1996A>G	p.Met666Val	missense	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.1996A>G	p.Met666Val	missense	Exon 8 of 8	ENSP00000332454.3	P57078-2
	RIPK4	ENST00000352483.3	TSL:5	c.2140A>G	p.Met714Val	missense	Exon 9 of 9	ENSP00000330161.2	P57078-1
	ENSG00000236883	ENST00000423276.1	TSL:3	n.350T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.978 AC: 148901 AN: 152204 Hom.: 72879 Cov.: 36

Gnomad AFR AF: 0.995

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.887

Gnomad FIN AF: 0.993

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.974

Gnomad OTH AF: 0.980

GnomAD2 exomes AF: 0.967 AC: 237922 AN: 246154 AF XY: 0.963

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 0.983

Gnomad EAS exome AF: 0.918

Gnomad FIN exome AF: 0.991

Gnomad NFE exome AF: 0.974

Gnomad OTH exome AF: 0.973

GnomAD4 exome AF: 0.968 AC: 1410648 AN: 1457906 Hom.: 682881 Cov.: 89 AF XY: 0.966 AC XY: 699989 AN XY: 724970

African (AFR) AF: 0.997 AC: 33323 AN: 33424

American (AMR) AF: 0.994 AC: 44269 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.984 AC: 25575 AN: 25992

East Asian (EAS) AF: 0.909 AC: 36039 AN: 39642

South Asian (SAS) AF: 0.897 AC: 77128 AN: 85954

European-Finnish (FIN) AF: 0.990 AC: 51253 AN: 51766

Middle Eastern (MID) AF: 0.974 AC: 5616 AN: 5764

European-Non Finnish (NFE) AF: 0.972 AC: 1079329 AN: 1110568

Other (OTH) AF: 0.965 AC: 58116 AN: 60240

GnomAD4 genome AF: 0.978 AC: 149018 AN: 152322 Hom.: 72936 Cov.: 36 AF XY: 0.978 AC XY: 72805 AN XY: 74480

African (AFR) AF: 0.995 AC: 41357 AN: 41584

American (AMR) AF: 0.991 AC: 15177 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 3408 AN: 3470

East Asian (EAS) AF: 0.919 AC: 4752 AN: 5170

South Asian (SAS) AF: 0.886 AC: 4274 AN: 4822

European-Finnish (FIN) AF: 0.993 AC: 10551 AN: 10626

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.974 AC: 66230 AN: 68020

Other (OTH) AF: 0.979 AC: 2070 AN: 2114

Alfa AF: 0.973 Hom.: 200594

Bravo AF: 0.981

TwinsUK AF: 0.973 AC: 3609

ALSPAC AF: 0.976 AC: 3760

ESP6500AA AF: 0.994 AC: 4380

ESP6500EA AF: 0.973 AC: 8366

ExAC AF: 0.965 AC: 116973

Asia WGS AF: 0.918 AC: 3193 AN: 3478

EpiCase AF: 0.972

EpiControl AF: 0.973

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
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.3
DANN	Benign	0.54
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.075	T
MetaRNN	Benign	6.0e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.65	N
PhyloP100		0.68
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.036
Sift	Benign	0.71	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.0060
MPC		0.43
ClinPred		0.000017	T
GERP RS		-0.094
Varity_R		0.044
gMVP		0.12
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: rs3746891; hg19: chr21-43161357; COSMIC: COSV60189370;