NM_199242.3:c.2782C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_199242.3(UNC13D):c.2782C>T(p.Arg928Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,588,302 control chromosomes in the GnomAD database, including 390 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R928H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 36 hom., cov: 33)

Exomes 𝑓: 0.021 ( 354 hom. )

Consequence

UNC13D
NM_199242.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.92

Publications

16 publications found

Variant links:

COSMIC-nc: COSV104392540

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008826911).

BP6

Variant 17-75830410-G-A is Benign according to our data. Variant chr17-75830410-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0173 (2628/152264) while in subpopulation AMR AF = 0.0256 (392/15296). AF 95% confidence interval is 0.0235. There are 36 homozygotes in GnomAd4. There are 1266 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.2782C>T	p.Arg928Cys	missense_variant	Exon 29 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.2782C>T	p.Arg928Cys	missense_variant	Exon 29 of 32	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2629

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0257

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0196

Gnomad FIN

AF:

0.0185

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0190

AC:

3894

AN:

205488

AF XY:

0.0198

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.0170

Gnomad EAS exome

AF:

0.0000639

Gnomad FIN exome

AF:

0.0223

Gnomad NFE exome

AF:

0.0252

Gnomad OTH exome

AF:

0.0214

GnomAD4 exome

AF:

0.0205

AC:

29491

AN:

1436038

Hom.:

354

Cov.:

AF XY:

0.0208

AC XY:

14828

AN XY:

712082

show subpopulations

African (AFR)

AF:

0.00332

AC:

110

AN:

33088

American (AMR)

AF:

0.0127

AC:

515

AN:

40608

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

409

AN:

25572

East Asian (EAS)

AF:

0.0000774

AC:

AN:

38754

South Asian (SAS)

AF:

0.0224

AC:

1842

AN:

82402

European-Finnish (FIN)

AF:

0.0209

AC:

1065

AN:

51030

Middle Eastern (MID)

AF:

0.0354

AC:

153

AN:

4318

European-Non Finnish (NFE)

AF:

0.0221

AC:

24285

AN:

1100930

Other (OTH)

AF:

0.0187

AC:

1109

AN:

59336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2023

4046

6068

8091

10114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

878

1756

2634

3512

4390

<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:

0.0173

AC:

2628

AN:

152264

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1266

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00332

AC:

138

AN:

41560

American (AMR)

AF:

0.0256

AC:

392

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.0201

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0185

AC:

196

AN:

10592

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0244

AC:

1657

AN:

68018

Other (OTH)

AF:

0.0222

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

133

265

398

530

663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0239

Hom.:

109

Bravo

AF:

0.0157

TwinsUK

AF:

0.0235

AC:

ALSPAC

AF:

0.0205

AC:

ESP6500AA

AF:

0.00296

AC:

ESP6500EA

AF:

0.0225

AC:

193

ExAC

AF:

0.0165

AC:

1984

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

UNC13D: PM5, BP4, BS1, BS2 -

Jun 20, 2023

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not present in FAST (due to DM? classification). ExAC: 4.7% (56/1194) Finnish -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hemophagocytic lymphohistiocytosis 3

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Jan 20, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.6

L;L

PhyloP100

2.9

PrimateAI

Benign

0.24

PROVEAN

Benign

1.6

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.13

T;T

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.41

B;.

Vest4

0.20

MPC

0.17

ClinPred

0.0075

GERP RS

2.9

PromoterAI

0.0018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.11

gMVP

0.45

Mutation Taster

=82/18

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over