chr17-75835577-A-G

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.1728-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,608,438 control chromosomes in the GnomAD database, including 20,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 7615 hom., cov: 33)

Exomes 𝑓: 0.093 ( 13037 hom. )

Consequence

UNC13D
NM_199242.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.114

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 17-75835577-A-G is Benign according to our data. Variant chr17-75835577-A-G is described in ClinVar as Benign. ClinVar VariationId is 263217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.1728-48T>C		intron_variant	Intron 19 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.1728-48T>C		intron_variant	Intron 19 of 31	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34519

AN:

152028

Hom.:

7596

Cov.:

show subpopulations

Gnomad AFR

AF:

0.574

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.329

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.0529

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.0683

Gnomad OTH

AF:

0.205

GnomAD2 exomes

AF:

0.139

AC:

33088

AN:

238450

AF XY:

0.132

show subpopulations

Gnomad AFR exome

AF:

0.590

Gnomad AMR exome

AF:

0.0925

Gnomad ASJ exome

AF:

0.157

Gnomad EAS exome

AF:

0.337

Gnomad FIN exome

AF:

0.0508

Gnomad NFE exome

AF:

0.0693

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.0932

AC:

135673

AN:

1456292

Hom.:

13037

Cov.:

AF XY:

0.0941

AC XY:

68176

AN XY:

724146

show subpopulations

African (AFR)

AF:

0.594

AC:

19790

AN:

33312

American (AMR)

AF:

0.0974

AC:

4287

AN:

44036

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

4038

AN:

26042

East Asian (EAS)

AF:

0.337

AC:

13261

AN:

39308

South Asian (SAS)

AF:

0.151

AC:

12896

AN:

85644

European-Finnish (FIN)

AF:

0.0533

AC:

2780

AN:

52142

Middle Eastern (MID)

AF:

0.248

AC:

1413

AN:

5704

European-Non Finnish (NFE)

AF:

0.0625

AC:

69390

AN:

1109962

Other (OTH)

AF:

0.130

AC:

7818

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

7384

14767

22151

29534

36918

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2976

5952

8928

11904

14880

<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:

0.227

AC:

34580

AN:

152146

Hom.:

7615

Cov.:

AF XY:

0.225

AC XY:

16739

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.574

AC:

23823

AN:

41504

American (AMR)

AF:

0.130

AC:

1984

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

618

AN:

3470

East Asian (EAS)

AF:

0.329

AC:

1698

AN:

5166

South Asian (SAS)

AF:

0.154

AC:

744

AN:

4822

European-Finnish (FIN)

AF:

0.0529

AC:

561

AN:

10610

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0683

AC:

4642

AN:

67970

Other (OTH)

AF:

0.202

AC:

428

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

1074

2147

3221

4294

5368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.152

Hom.:

711

Bravo

AF:

0.250

Asia WGS

AF:

0.231

AC:

804

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 12, 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

-0.93

CADD

Benign

2.7

(source)

DANN

Benign

0.47

PhyloP100

0.11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=4/96

disease causing

(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