Genetic Variant UNC13A:p.Arg1641His (chr19-17606244-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001080421.3(UNC13A):c.4922G>A(p.Arg1641His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,548,404 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 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

UNC13A
NM_001080421.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.27

Publications

0 publications found

Variant links:

Genes affected

UNC13A (HGNC:23150): (unc-13 homolog A) This gene encodes a member of the UNC13 family. UNC13 proteins bind to phorbol esters and diacylglycerol and play important roles in neurotransmitter release at synapses. Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis. [provided by RefSeq, Feb 2012]

UNC13A Gene-Disease associations (from GenCC):

congenital nervous system disorder
Inheritance: Unknown Classification: LIMITED Submitted by: Illumina, ClinGen

UNC13A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10095981).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080421.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UNC13A	NM_001080421.3	MANE Select	c.4922G>A	p.Arg1641His	missense	Exon 44 of 44	NP_001073890.2	Q9UPW8
UNC13A	NM_001387021.1		c.4910G>A	p.Arg1637His	missense	Exon 42 of 42	NP_001373950.1
UNC13A	NM_001387022.1		c.4907G>A	p.Arg1636His	missense	Exon 42 of 42	NP_001373951.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UNC13A	ENST00000519716.7	TSL:5 MANE Select	c.4922G>A	p.Arg1641His	missense	Exon 44 of 44	ENSP00000429562.2	Q9UPW8
UNC13A	ENST00000551649.5	TSL:5	c.4979G>A	p.Arg1660His	missense	Exon 45 of 45	ENSP00000447236.1	F8W059
UNC13A	ENST00000552293.5	TSL:5	c.4904G>A	p.Arg1635His	missense	Exon 42 of 42	ENSP00000447572.1	F8W0P6

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000561

AC:

AN:

142666

AF XY:

0.0000902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000153

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000189

AC:

264

AN:

1396164

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

133

AN XY:

688884

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30824

American (AMR)

AF:

0.00

AC:

AN:

35852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25096

East Asian (EAS)

AF:

0.00

AC:

AN:

35352

South Asian (SAS)

AF:

0.00

AC:

AN:

79318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

0.000228

AC:

246

AN:

1078790

Other (OTH)

AF:

0.000311

AC:

AN:

57892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

AF:

0.0000394

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000906

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000196

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.012

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

1.3

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.051

Sift

Benign

0.037

Sift4G

Uncertain

0.056

Polyphen

0.081

Vest4

0.18

MutPred

0.44

Loss of MoRF binding (P = 0.0775)

MVP

0.16

MPC

1.5

ClinPred

0.24

GERP RS

1.9

Varity_R

0.12

gMVP

0.44

Mutation Taster

=90/10

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over