17-75836662-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_199242.3(UNC13D):c.1208T>C(p.Leu403Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

UNC13D
NM_199242.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.37

Publications

5 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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 17-75836662-A-G is Pathogenic according to our data. Variant chr17-75836662-A-G is described in CliVar as Pathogenic. Clinvar id is 2002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75836662-A-G is described in CliVar as Pathogenic. Clinvar id is 2002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75836662-A-G is described in CliVar as Pathogenic. Clinvar id is 2002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75836662-A-G is described in CliVar as Pathogenic. Clinvar id is 2002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75836662-A-G is described in CliVar as Pathogenic. Clinvar id is 2002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75836662-A-G is described in CliVar as Pathogenic. Clinvar id is 2002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75836662-A-G is described in CliVar as Pathogenic. Clinvar id is 2002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75836662-A-G is described in CliVar as Pathogenic. Clinvar id is 2002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75836662-A-G is described in CliVar as Pathogenic. Clinvar id is 2002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75836662-A-G is described in CliVar as Pathogenic. Clinvar id is 2002.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.1208T>C	p.Leu403Pro	missense_variant	Exon 14 of 32	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.1208T>C	p.Leu403Pro	missense_variant	Exon 14 of 32	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461438

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3

Pathogenic:1

Jan 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Familial hemophagocytic lymphohistiocytosis

Pathogenic:1

Jun 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: UNC13D c.1208T>C (p.Leu403Pro) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 250864 control chromosomes. c.1208T>C has been observed in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g., Bahadir_2022, Platt_2021, Sieni_2011, ZurStadt_2006). Publications have reported experimental evidence evaluating an impact on protein function that demonstrate this variant results in absent activity compared to wild-type (ZurStadt_2006, Noori_2023). The following publications have been ascertained in the context of this evaluation (PMID: 35293882, 36706356, 32888943, 21248318, 16278825). ClinVar contains an entry for this variant (Variation ID: 2002). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.043

MutationAssessor

Benign

2.0

M;M

PhyloP100

7.4

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.5

D;D

REVEL

Pathogenic

0.73

Sift

Benign

0.14

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.87

Loss of stability (P = 0.0123);Loss of stability (P = 0.0123);

MVP

0.83

MPC

0.64

ClinPred

0.99

GERP RS

3.2

Varity_R

0.77

gMVP

0.84

Mutation Taster

=14/86

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over