rs35628234

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_199242.3(UNC13D):c.2943G>A(p.Glu981Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0494 in 1,577,316 control chromosomes in the GnomAD database, including 2,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.071 ( 558 hom., cov: 32)

Exomes 𝑓: 0.047 ( 2009 hom. )

Consequence

UNC13D
NM_199242.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.18

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 17-75830039-C-T is Benign according to our data. Variant chr17-75830039-C-T is described in ClinVar as Benign. ClinVar VariationId is 263238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.18 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.2943G>A	p.Glu981Glu	synonymous_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.2943G>A	p.Glu981Glu	synonymous_variant	Exon 30 of 32	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.0713

AC:

10845

AN:

152156

Hom.:

553

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0430

Gnomad ASJ

AF:

0.0634

Gnomad EAS

AF:

0.0260

Gnomad SAS

AF:

0.0835

Gnomad FIN

AF:

0.0342

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0454

Gnomad OTH

AF:

0.0592

GnomAD2 exomes

AF:

0.0516

AC:

9828

AN:

190444

AF XY:

0.0536

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.0232

Gnomad ASJ exome

AF:

0.0588

Gnomad EAS exome

AF:

0.0270

Gnomad FIN exome

AF:

0.0336

Gnomad NFE exome

AF:

0.0429

Gnomad OTH exome

AF:

0.0516

GnomAD4 exome

AF:

0.0471

AC:

67125

AN:

1425042

Hom.:

2009

Cov.:

AF XY:

0.0485

AC XY:

34184

AN XY:

705126

show subpopulations

African (AFR)

AF:

0.148

AC:

4902

AN:

33012

American (AMR)

AF:

0.0262

AC:

1005

AN:

38360

Ashkenazi Jewish (ASJ)

AF:

0.0575

AC:

1455

AN:

25326

East Asian (EAS)

AF:

0.0375

AC:

1441

AN:

38434

South Asian (SAS)

AF:

0.0903

AC:

7317

AN:

80986

European-Finnish (FIN)

AF:

0.0357

AC:

1814

AN:

50854

Middle Eastern (MID)

AF:

0.0717

AC:

410

AN:

5720

European-Non Finnish (NFE)

AF:

0.0417

AC:

45643

AN:

1093308

Other (OTH)

AF:

0.0531

AC:

3138

AN:

59042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

4099

8199

12298

16398

20497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1788

3576

5364

7152

8940

<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:

0.0713

AC:

10862

AN:

152274

Hom.:

558

Cov.:

AF XY:

0.0709

AC XY:

5275

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.141

AC:

5850

AN:

41540

American (AMR)

AF:

0.0430

AC:

657

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0634

AC:

220

AN:

3470

East Asian (EAS)

AF:

0.0261

AC:

135

AN:

5176

South Asian (SAS)

AF:

0.0838

AC:

405

AN:

4832

European-Finnish (FIN)

AF:

0.0342

AC:

363

AN:

10622

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0454

AC:

3086

AN:

68024

Other (OTH)

AF:

0.0581

AC:

123

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

496

992

1489

1985

2481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0597

Hom.:

213

Bravo

AF:

0.0730

Asia WGS

AF:

0.0570

AC:

200

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

9.0

(source)

DANN

Benign

0.85

PhyloP100

1.2

PromoterAI

-0.026

Neutral

(source)

Mutation Taster

=99/1

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