chr17-75844162-G-A

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.117+59C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,589,986 control chromosomes in the GnomAD database, including 53,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8244 hom., cov: 32)

Exomes 𝑓: 0.24 ( 44788 hom. )

Consequence

UNC13D
NM_199242.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.50

Publications

8 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=-0.81).

BP6

Variant 17-75844162-G-A is Benign according to our data. Variant chr17-75844162-G-A is described in ClinVar as Benign. ClinVar VariationId is 1166947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.117+59C>T		intron_variant	Intron 1 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.117+59C>T		intron_variant	Intron 1 of 31	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46186

AN:

151932

Hom.:

8216

Cov.:

show subpopulations

Gnomad AFR

AF:

0.491

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.233

Gnomad ASJ

AF:

0.316

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.175

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.248

Gnomad OTH

AF:

0.303

GnomAD4 exome

AF:

0.243

AC:

349789

AN:

1437936

Hom.:

44788

Cov.:

AF XY:

0.242

AC XY:

173596

AN XY:

716068

show subpopulations

African (AFR)

AF:

0.501

AC:

16622

AN:

33184

American (AMR)

AF:

0.202

AC:

9033

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

8144

AN:

26048

East Asian (EAS)

AF:

0.111

AC:

4399

AN:

39572

South Asian (SAS)

AF:

0.216

AC:

18593

AN:

85962

European-Finnish (FIN)

AF:

0.178

AC:

7529

AN:

42396

Middle Eastern (MID)

AF:

0.346

AC:

1956

AN:

5660

European-Non Finnish (NFE)

AF:

0.243

AC:

267854

AN:

1100674

Other (OTH)

AF:

0.262

AC:

15659

AN:

59804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

13763

27526

41289

55052

68815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9234

18468

27702

36936

46170

<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:

46264

AN:

152050

Hom.:

8244

Cov.:

AF XY:

0.296

AC XY:

21978

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.491

AC:

20366

AN:

41450

American (AMR)

AF:

0.233

AC:

3559

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

1098

AN:

3472

East Asian (EAS)

AF:

0.116

AC:

599

AN:

5166

South Asian (SAS)

AF:

0.203

AC:

977

AN:

4814

European-Finnish (FIN)

AF:

0.175

AC:

1850

AN:

10588

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.248

AC:

16831

AN:

67954

Other (OTH)

AF:

0.310

AC:

654

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1515

3030

4545

6060

7575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<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:

0.271

Hom.:

1955

Bravo

AF:

0.319

Asia WGS

AF:

0.215

AC:

745

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

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 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

Familial hemophagocytic lymphohistiocytosis 3

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Autoinflammatory syndrome

Benign:1

Dec 12, 2016

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.51

(source)

DANN

Benign

0.73

PhyloP100

-1.5

PromoterAI

-0.072

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