rs9904366

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_199242.3(UNC13D):c.175G>A(p.Ala59Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,609,142 control chromosomes in the GnomAD database, including 408 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A59A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 41 hom., cov: 33)

Exomes 𝑓: 0.014 ( 367 hom. )

Consequence

UNC13D
NM_199242.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 1.87

Publications

21 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, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044733584).

BP6

Variant 17-75843245-C-T is Benign according to our data. Variant chr17-75843245-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263219.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199242.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	NM_199242.3	MANE Select	c.175G>A	p.Ala59Thr	missense	Exon 3 of 32	NP_954712.1	Q70J99-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.175G>A	p.Ala59Thr	missense	Exon 3 of 32	ENSP00000207549.3	Q70J99-1
UNC13D	ENST00000412096.6	TSL:2	c.175G>A	p.Ala59Thr	missense	Exon 3 of 33	ENSP00000388093.1	Q70J99-3
UNC13D	ENST00000868100.1		c.175G>A	p.Ala59Thr	missense	Exon 4 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2208

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0129

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0164

Gnomad ASJ

AF:

0.0735

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0136

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0159

AC:

3919

AN:

246844

AF XY:

0.0171

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.0633

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.0250

GnomAD4 exome

AF:

0.0141

AC:

20517

AN:

1457032

Hom.:

367

Cov.:

AF XY:

0.0148

AC XY:

10755

AN XY:

725024

show subpopulations

African (AFR)

AF:

0.0168

AC:

562

AN:

33476

American (AMR)

AF:

0.0152

AC:

681

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0625

AC:

1633

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0206

AC:

1774

AN:

86254

European-Finnish (FIN)

AF:

0.00150

AC:

AN:

48746

Middle Eastern (MID)

AF:

0.132

AC:

753

AN:

5714

European-Non Finnish (NFE)

AF:

0.0124

AC:

13806

AN:

1111940

Other (OTH)

AF:

0.0204

AC:

1233

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

1221

2442

3662

4883

6104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

530

1060

1590

2120

2650

<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:

0.0145

AC:

2204

AN:

152110

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1040

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0129

AC:

536

AN:

41516

American (AMR)

AF:

0.0164

AC:

251

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0735

AC:

255

AN:

3470

East Asian (EAS)

AF:

0.000582

AC:

AN:

5152

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4820

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0136

AC:

927

AN:

67948

Other (OTH)

AF:

0.0294

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

110

221

331

442

552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0167

Hom.:

119

Bravo

AF:

0.0163

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.0171

AC:

147

ExAC

AF:

0.0158

AC:

1912

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0219

EpiControl

AF:

0.0229

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial hemophagocytic lymphohistiocytosis 3 (3)

not specified (2)

Autoinflammatory syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.7

PhyloP100

1.9

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

REVEL

Benign

0.075

Sift

Benign

0.041

Sift4G

Benign

0.35

Polyphen

0.0050

Vest4

0.079

MPC

0.095

ClinPred

0.0082

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

gMVP

0.27

Mutation Taster

=86/14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over