17-75843285-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_199242.3(UNC13D):c.154-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,602,580 control chromosomes in the GnomAD database, including 55,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8145 hom., cov: 32)

Exomes 𝑓: 0.25 ( 47458 hom. )

Consequence

UNC13D
NM_199242.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.442

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 17-75843285-C-T is Benign according to our data. Variant chr17-75843285-C-T is described in ClinVar as Benign. ClinVar VariationId is 263214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.154-19G>A		intron_variant	Intron 2 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.154-19G>A		intron_variant	Intron 2 of 31	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46174

AN:

151894

Hom.:

8116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.480

Gnomad AMI

AF:

0.252

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.291

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.180

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.257

Gnomad OTH

AF:

0.301

GnomAD2 exomes

AF:

0.244

AC:

58503

AN:

239842

AF XY:

0.242

show subpopulations

Gnomad AFR exome

AF:

0.492

Gnomad AMR exome

AF:

0.198

Gnomad ASJ exome

AF:

0.298

Gnomad EAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.187

Gnomad NFE exome

AF:

0.254

Gnomad OTH exome

AF:

0.252

GnomAD4 exome

AF:

0.251

AC:

363713

AN:

1450568

Hom.:

47458

Cov.:

AF XY:

0.249

AC XY:

180061

AN XY:

721984

show subpopulations

African (AFR)

AF:

0.486

AC:

16261

AN:

33448

American (AMR)

AF:

0.202

AC:

9008

AN:

44580

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

7812

AN:

26126

East Asian (EAS)

AF:

0.108

AC:

4268

AN:

39664

South Asian (SAS)

AF:

0.220

AC:

18982

AN:

86182

European-Finnish (FIN)

AF:

0.185

AC:

8021

AN:

43408

Middle Eastern (MID)

AF:

0.261

AC:

1444

AN:

5540

European-Non Finnish (NFE)

AF:

0.254

AC:

282256

AN:

1111378

Other (OTH)

AF:

0.260

AC:

15661

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

16834

33669

50503

67338

84172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9634

19268

28902

38536

48170

<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:

0.304

AC:

46247

AN:

152012

Hom.:

8145

Cov.:

AF XY:

0.295

AC XY:

21941

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.480

AC:

19877

AN:

41414

American (AMR)

AF:

0.227

AC:

3472

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

1011

AN:

3470

East Asian (EAS)

AF:

0.116

AC:

598

AN:

5170

South Asian (SAS)

AF:

0.208

AC:

1001

AN:

4820

European-Finnish (FIN)

AF:

0.180

AC:

1904

AN:

10584

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.257

AC:

17433

AN:

67956

Other (OTH)

AF:

0.308

AC:

652

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1586

3173

4759

6346

7932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

442

884

1326

1768

2210

<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:

0.206

Hom.:

651

Bravo

AF:

0.318

Asia WGS

AF:

0.214

AC:

745

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 12, 2023

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 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial hemophagocytic lymphohistiocytosis 3

Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.78

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.44

PromoterAI

-0.0080

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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