Variant chr5-176868962-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_133369.3(UNC5A):c.719A>G(p.Tyr240Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

UNC5A
NM_133369.3 missense, splice_region

Scores

Splicing: ADA: 0.04329

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.38

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC5A	NM_133369.3 linkuse as main transcript	c.719A>G	p.Tyr240Cys	missense_variant, splice_region_variant	5/15	ENST00000329542.9	NP_588610.2	Q6ZN44-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
UNC5A	ENST00000329542.9 linkuse as main transcript	c.719A>G	p.Tyr240Cys	missense_variant, splice_region_variant	5/15	1	NM_133369.3	ENSP00000332737.4	Q6ZN44-1
UNC5A	ENST00000513890.1 linkuse as main transcript	n.*771A>G		splice_region_variant, non_coding_transcript_exon_variant	6/9	1		ENSP00000424067.1	H0Y9G2
UNC5A	ENST00000513890.1 linkuse as main transcript	n.*771A>G		3_prime_UTR_variant	6/9	1		ENSP00000424067.1	H0Y9G2
UNC5A	ENST00000509580.2 linkuse as main transcript	c.719A>G	p.Tyr240Cys	missense_variant, splice_region_variant	5/16	5		ENSP00000421795.2	H0Y8R2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447676

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718582

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:

9.06e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

May 13, 2024

The c.719A>G (p.Y240C) alteration is located in exon 5 (coding exon 5) of the UNC5A gene. This alteration results from a A to G substitution at nucleotide position 719, causing the tyrosine (Y) at amino acid position 240 to be replaced by a cysteine (C). 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

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.1

L;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.2

D;.

REVEL

Uncertain

0.31

Sift

Benign

0.17

T;.

Sift4G

Uncertain

0.046

D;.

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.51

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);

MVP

0.54

MPC

1.6

ClinPred

0.99

GERP RS

4.5

Varity_R

0.65

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.043

dbscSNV1_RF

Benign

0.31

SpliceAI score (max)

0.070

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