Genetic Variant UNC50:p.Tyr55Cys (chr2-98609923-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014044.7(UNC50):c.164A>G(p.Tyr55Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

UNC50
NM_014044.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.77

Publications

0 publications found

Variant links:

Genes affected

UNC50 (HGNC:16046): (unc-50 inner nuclear membrane RNA binding protein) Predicted to enable RNA binding activity. Predicted to be involved in protein localization to cell surface. Predicted to be located in Golgi apparatus and nuclear inner membrane. Predicted to be integral component of Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

UNC50 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC50	NM_014044.7 link	c.164A>G	p.Tyr55Cys	missense_variant	Exon 2 of 6	ENST00000357765.7	NP_054763.2	Q53HI1A0A0S2Z612
UNC50	NM_001330354.2 link	c.215A>G	p.Tyr72Cys	missense_variant	Exon 2 of 6		NP_001317283.1	J3KQ47
UNC50	NM_001330353.2 link	c.164A>G	p.Tyr55Cys	missense_variant	Exon 2 of 6		NP_001317282.1
UNC50	XM_006712403.4 link	c.215A>G	p.Tyr72Cys	missense_variant	Exon 2 of 6		XP_006712466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UNC50	ENST00000357765.7 link	c.164A>G	p.Tyr55Cys	missense_variant	Exon 2 of 6	1	NM_014044.7	ENSP00000350409.2	Q53HI1
UNC50	ENST00000409347.5 link	c.215A>G	p.Tyr72Cys	missense_variant	Exon 2 of 6	1		ENSP00000386466.1	J3KQ47
UNC50	ENST00000409975.5 link	c.215A>G	p.Tyr72Cys	missense_variant	Exon 1 of 5	1		ENSP00000387146.1	J3KQ47

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 20, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.164A>G (p.Y55C) alteration is located in exon 2 (coding exon 1) of the UNC50 gene. This alteration results from a A to G substitution at nucleotide position 164, causing the tyrosine (Y) at amino acid position 55 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

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

0.0086

MutationAssessor

Pathogenic

3.3

M;.;.

PhyloP100

8.8

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.9

D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.96

MutPred

0.72

Gain of catalytic residue at L56 (P = 0.0119);.;.;

MVP

0.51

MPC

1.4

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.78

Mutation Taster

=14/86

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over