Variant 6-41032964-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173561.3(UNC5CL):c.869G>A(p.Arg290His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,602,802 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

UNC5CL
NM_173561.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.45

Variant links:

Genes affected

UNC5CL (HGNC:21203): (unc-5 family C-terminal like) Enables peptidase activity. Acts upstream of or within positive regulation of I-kappaB kinase/NF-kappaB signaling and positive regulation of JNK cascade. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

UNC5CL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC5CL	NM_173561.3 linkuse as main transcript	c.869G>A	p.Arg290His	missense_variant	4/9	ENST00000244565.8	NP_775832.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
UNC5CL	ENST00000244565.8 linkuse as main transcript	c.869G>A	p.Arg290His	missense_variant	4/9	1	NM_173561.3	ENSP00000244565	P1
UNC5CL	ENST00000373164.1 linkuse as main transcript	c.869G>A	p.Arg290His	missense_variant	3/8	1		ENSP00000362258	P1
UNC5CL	ENST00000470102.1 linkuse as main transcript	n.24G>A		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000485

AC:

AN:

226732

Hom.:

AF XY:

0.0000572

AC XY:

AN XY:

122336

show subpopulations

Gnomad AFR exome

AF:

0.0000715

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000296

Gnomad SAS exome

AF:

0.000143

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000987

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1450528

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

720426

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.000178

Gnomad4 SAS exome

AF:

0.000142

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000573

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000660

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.869G>A (p.R290H) alteration is located in exon 4 (coding exon 3) of the UNC5CL gene. This alteration results from a G to A substitution at nucleotide position 869, causing the arginine (R) at amino acid position 290 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0058

T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

0.028

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.76

T;.

M_CAP

Benign

0.0026

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

L;L

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.92

N;N

REVEL

Benign

0.025

Sift

Benign

0.31

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.018

B;B

Vest4

0.44

MutPred

0.40

Loss of methylation at R290 (P = 0.009);Loss of methylation at R290 (P = 0.009);

MVP

0.67

MPC

0.15

ClinPred

0.042

GERP RS

4.6

Varity_R

0.062

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: 7

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over