Genetic Variant UNC5A:p.Arg185Gln (chr5-176868797-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_133369.3(UNC5A):c.554G>A(p.Arg185Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000025 in 1,599,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

UNC5A
NM_133369.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.18

Variant links:

Genes affected

UNC5A (HGNC:12567): (unc-5 netrin receptor A) UNC5A belongs to a family of netrin-1 (MIM 601614) receptors thought to mediate the chemorepulsive effect of netrin-1 on specific axons. For more information on UNC5 proteins, see UNC5C (MIM 603610).[supplied by OMIM, Apr 2004]

UNC5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28445497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC5A	NM_133369.3 link	c.554G>A	p.Arg185Gln	missense_variant	Exon 5 of 15	ENST00000329542.9	NP_588610.2	Q6ZN44-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UNC5A	ENST00000329542.9 link	c.554G>A	p.Arg185Gln	missense_variant	Exon 5 of 15	1	NM_133369.3	ENSP00000332737.4	Q6ZN44-1
UNC5A	ENST00000513890.1 link	n.*606G>A		non_coding_transcript_exon_variant	Exon 6 of 9	1		ENSP00000424067.1	H0Y9G2
UNC5A	ENST00000513890.1 link	n.*606G>A		3_prime_UTR_variant	Exon 6 of 9	1		ENSP00000424067.1	H0Y9G2
UNC5A	ENST00000509580.2 link	c.554G>A	p.Arg185Gln	missense_variant	Exon 5 of 16	5		ENSP00000421795.2	H0Y8R2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1447076

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

716898

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000272

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.554G>A (p.R185Q) alteration is located in exon 5 (coding exon 5) of the UNC5A gene. This alteration results from a G to A substitution at nucleotide position 554, causing the arginine (R) at amino acid position 185 to be replaced by a glutamine (Q). 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

0.28

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.22

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0070

D;.

Polyphen

0.97

D;.

Vest4

0.70

MutPred

0.60

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.36

MPC

1.6

ClinPred

0.91

GERP RS

3.6

Varity_R

0.46

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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