rs760552006

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_199242.3(UNC13D):c.2795T>C(p.Leu932Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,590,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

UNC13D
NM_199242.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.98

Publications

1 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: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000313 (45/1438062) while in subpopulation AMR AF = 0.00103 (42/40944). AF 95% confidence interval is 0.000779. There are 0 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2795T>C	p.Leu932Pro	missense	Exon 29 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.2795T>C	p.Leu932Pro	missense	Exon 29 of 32	ENSP00000207549.3	Q70J99-1
UNC13D	ENST00000412096.6	TSL:2	c.2795T>C	p.Leu932Pro	missense	Exon 29 of 33	ENSP00000388093.1	Q70J99-3
UNC13D	ENST00000868100.1		c.2795T>C	p.Leu932Pro	missense	Exon 30 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000186

AC:

AN:

209704

AF XY:

0.0000796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000190

GnomAD4 exome

AF:

0.0000313

AC:

AN:

1438062

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

713258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33140

American (AMR)

AF:

0.00103

AC:

AN:

40944

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25582

East Asian (EAS)

AF:

0.00

AC:

AN:

38870

South Asian (SAS)

AF:

0.00

AC:

AN:

82584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4188

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102222

Other (OTH)

AF:

0.0000505

AC:

AN:

59386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000748

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial hemophagocytic lymphohistiocytosis 3 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

3.5

PhyloP100

8.0

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MutPred

0.77

Loss of stability (P = 0.0419)

MVP

0.88

MPC

0.64

ClinPred

0.70

GERP RS

4.8

PromoterAI

0.014

Neutral

(source)

Varity_R

0.99

gMVP

0.85

Mutation Taster

=18/82

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over