Genetic Variant UNC13D:c.117+30G>A (chr17-75844191-C-T) – ACMG Classification: Benign (-20 pts)

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+30G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,607,184 control chromosomes in the GnomAD database, including 6,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1327 hom., cov: 32)

Exomes 𝑓: 0.061 ( 5089 hom. )

Consequence

UNC13D
NM_199242.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.57

Publications

7 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=-0.8).

BP6

Variant 17-75844191-C-T is Benign according to our data. Variant chr17-75844191-C-T is described in ClinVar as Benign. ClinVar VariationId is 263211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.117+30G>A		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+30G>A		intron_variant	Intron 1 of 31	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15837

AN:

152088

Hom.:

1328

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0598

Gnomad ASJ

AF:

0.0611

Gnomad EAS

AF:

0.308

Gnomad SAS

AF:

0.121

Gnomad FIN

AF:

0.0494

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0478

Gnomad OTH

AF:

0.0947

GnomAD2 exomes

AF:

0.0857

AC:

20959

AN:

244680

AF XY:

0.0851

show subpopulations

Gnomad AFR exome

AF:

0.214

Gnomad AMR exome

AF:

0.0301

Gnomad ASJ exome

AF:

0.0531

Gnomad EAS exome

AF:

0.318

Gnomad FIN exome

AF:

0.0449

Gnomad NFE exome

AF:

0.0467

Gnomad OTH exome

AF:

0.0721

GnomAD4 exome

AF:

0.0612

AC:

89064

AN:

1454978

Hom.:

5089

Cov.:

AF XY:

0.0628

AC XY:

45445

AN XY:

724104

show subpopulations

African (AFR)

AF:

0.214

AC:

7173

AN:

33442

American (AMR)

AF:

0.0323

AC:

1442

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0533

AC:

1393

AN:

26118

East Asian (EAS)

AF:

0.324

AC:

12855

AN:

39690

South Asian (SAS)

AF:

0.119

AC:

10237

AN:

86240

European-Finnish (FIN)

AF:

0.0481

AC:

2293

AN:

47714

Middle Eastern (MID)

AF:

0.0937

AC:

538

AN:

5744

European-Non Finnish (NFE)

AF:

0.0437

AC:

48562

AN:

1111020

Other (OTH)

AF:

0.0758

AC:

4571

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

4256

8512

12768

17024

21280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2046

4092

6138

8184

10230

<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:

0.104

AC:

15842

AN:

152206

Hom.:

1327

Cov.:

AF XY:

0.106

AC XY:

7900

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.206

AC:

8550

AN:

41504

American (AMR)

AF:

0.0597

AC:

914

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0611

AC:

212

AN:

3472

East Asian (EAS)

AF:

0.307

AC:

1584

AN:

5154

South Asian (SAS)

AF:

0.121

AC:

582

AN:

4814

European-Finnish (FIN)

AF:

0.0494

AC:

525

AN:

10626

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0478

AC:

3252

AN:

68018

Other (OTH)

AF:

0.0928

AC:

196

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

659

1317

1976

2634

3293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

174

348

522

696

870

<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:

0.0684

Hom.:

269

Bravo

AF:

0.111

Asia WGS

AF:

0.190

AC:

660

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.80

CADD

Benign

0.80

(source)

DANN

Benign

0.66

PhyloP100

-3.6

PromoterAI

0.0076

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