Genetic Variant UNC13D:p.Ala965Ser (chr17-75830089-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_199242.3(UNC13D):c.2893G>T(p.Ala965Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A965T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

UNC13D
NM_199242.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.94

Publications

5 publications found

Variant links:

Genes affected

UNC13D (HGNC:23147): (unc-13 homolog D) This gene encodes a protein that is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-terminal phorbol ester-binding C1 domain present in other Munc13 proteins. The protein appears to play a role in vesicle maturation during exocytosis and is involved in regulation of cytolytic granules secretion. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3, a genetically heterogeneous, rare autosomal recessive disorder. [provided by RefSeq, Jul 2008]

UNC13D Gene-Disease associations (from GenCC):

familial hemophagocytic lymphohistiocytosis 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
hereditary hemophagocytic lymphohistiocytosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

UNC13D links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09159258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.2893G>T	p.Ala965Ser	missense_variant	Exon 30 of 32	ENST00000207549.9	NP_954712.1	Q70J99-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9 link	c.2893G>T	p.Ala965Ser	missense_variant	Exon 30 of 32	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

194524

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1428504

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707284

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32898

American (AMR)

AF:

0.00

AC:

AN:

39192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25400

East Asian (EAS)

AF:

0.00

AC:

AN:

38214

South Asian (SAS)

AF:

0.00

AC:

AN:

81450

European-Finnish (FIN)

AF:

0.0000196

AC:

AN:

51016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095420

Other (OTH)

AF:

0.00

AC:

AN:

59190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.059

T;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.092

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.3

N;N

PhyloP100

1.9

PrimateAI

Benign

0.41

PROVEAN

Benign

0.84

N;N

REVEL

Benign

0.085

Sift

Benign

1.0

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.064

B;.

Vest4

0.16

MutPred

0.32

Gain of phosphorylation at A965 (P = 0.0243);Gain of phosphorylation at A965 (P = 0.0243);

MVP

0.69

MPC

0.13

ClinPred

0.12

GERP RS

4.3

PromoterAI

0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.037

gMVP

0.23

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over