17-75831355-CG-CGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_199242.3(UNC13D):c.2448-8dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,609,058 control chromosomes in the GnomAD database, including 22,339 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 8033 hom., cov: 28)

Exomes 𝑓: 0.099 ( 14306 hom. )

Consequence

UNC13D
NM_199242.3 splice_region, intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: -0.316

Publications

3 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:

ENSG00000302174 (HGNC:):

ENSG00000302174 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 17-75831355-C-CG is Benign according to our data. Variant chr17-75831355-C-CG is described in CliVar as Benign. Clinvar id is 263226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75831355-C-CG is described in CliVar as Benign. Clinvar id is 263226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75831355-C-CG is described in CliVar as Benign. Clinvar id is 263226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75831355-C-CG is described in CliVar as Benign. Clinvar id is 263226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75831355-C-CG is described in CliVar as Benign. Clinvar id is 263226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75831355-C-CG is described in CliVar as Benign. Clinvar id is 263226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75831355-C-CG is described in CliVar as Benign. Clinvar id is 263226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75831355-C-CG is described in CliVar as Benign. Clinvar id is 263226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.2448-8dupC		splice_region_variant, intron_variant	Intron 25 of 31	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.2448-8dupC		splice_region_variant, intron_variant	Intron 25 of 31	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

35625

AN:

151958

Hom.:

8007

Cov.:

show subpopulations

Gnomad AFR

AF:

0.587

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.326

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.0549

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.0731

Gnomad OTH

AF:

0.216

GnomAD2 exomes

AF:

0.147

AC:

35586

AN:

242408

AF XY:

0.141

show subpopulations

Gnomad AFR exome

AF:

0.605

Gnomad AMR exome

AF:

0.0971

Gnomad ASJ exome

AF:

0.183

Gnomad EAS exome

AF:

0.333

Gnomad FIN exome

AF:

0.0530

Gnomad NFE exome

AF:

0.0747

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.0992

AC:

144541

AN:

1456982

Hom.:

14306

Cov.:

AF XY:

0.101

AC XY:

72890

AN XY:

724952

show subpopulations

African (AFR)

AF:

0.608

AC:

20343

AN:

33440

American (AMR)

AF:

0.102

AC:

4556

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

4738

AN:

26100

East Asian (EAS)

AF:

0.340

AC:

13478

AN:

39676

South Asian (SAS)

AF:

0.167

AC:

14388

AN:

86198

European-Finnish (FIN)

AF:

0.0555

AC:

2742

AN:

49396

Middle Eastern (MID)

AF:

0.261

AC:

1500

AN:

5758

European-Non Finnish (NFE)

AF:

0.0671

AC:

74539

AN:

1111438

Other (OTH)

AF:

0.137

AC:

8257

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

6727

13454

20181

26908

33635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3174

6348

9522

12696

15870

<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:

0.235

AC:

35692

AN:

152076

Hom.:

8033

Cov.:

AF XY:

0.232

AC XY:

17240

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.587

AC:

24345

AN:

41454

American (AMR)

AF:

0.135

AC:

2060

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

701

AN:

3470

East Asian (EAS)

AF:

0.326

AC:

1679

AN:

5152

South Asian (SAS)

AF:

0.169

AC:

816

AN:

4816

European-Finnish (FIN)

AF:

0.0549

AC:

582

AN:

10606

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0731

AC:

4971

AN:

67978

Other (OTH)

AF:

0.214

AC:

453

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1017

2034

3050

4067

5084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.161

Hom.:

742

Bravo

AF:

0.258

EpiCase

AF:

0.0856

EpiControl

AF:

0.0853

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Familial hemophagocytic lymphohistiocytosis 3

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hemophagocytic lymphohistiocytosis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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