rs372034111

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_199242.3(UNC13D):c.3078C>T(p.Pro1026Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,595,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. P1026P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

UNC13D
NM_199242.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -7.09

Publications

0 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 17-75828860-G-A is Benign according to our data. Variant chr17-75828860-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263239.

BP7

Synonymous conserved (PhyloP=-7.09 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000203 (293/1443550) while in subpopulation AFR AF = 0.00099 (33/33336). AF 95% confidence interval is 0.000724. There are 1 homozygotes in GnomAdExome4. There are 136 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.3078C>T	p.Pro1026Pro	synonymous	Exon 31 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.3078C>T	p.Pro1026Pro	synonymous	Exon 31 of 32	ENSP00000207549.3	Q70J99-1
UNC13D	ENST00000412096.6	TSL:2	c.3078C>T	p.Pro1026Pro	synonymous	Exon 31 of 33	ENSP00000388093.1	Q70J99-3
UNC13D	ENST00000868100.1		c.3078C>T	p.Pro1026Pro	synonymous	Exon 32 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes

AF:

0.000499

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000287

AC:

AN:

212484

AF XY:

0.000282

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000128

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000612

Gnomad FIN exome

AF:

0.00192

Gnomad NFE exome

AF:

0.000161

Gnomad OTH exome

AF:

0.000741

GnomAD4 exome

AF:

0.000203

AC:

293

AN:

1443550

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

136

AN XY:

717272

show subpopulations

African (AFR)

AF:

0.000990

AC:

AN:

33336

American (AMR)

AF:

0.000190

AC:

AN:

42044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25836

East Asian (EAS)

AF:

0.000102

AC:

AN:

39058

South Asian (SAS)

AF:

0.0000592

AC:

AN:

84524

European-Finnish (FIN)

AF:

0.00194

AC:

AN:

48002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5254

European-Non Finnish (NFE)

AF:

0.000121

AC:

134

AN:

1105782

Other (OTH)

AF:

0.000268

AC:

AN:

59714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000499

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41578

American (AMR)

AF:

0.000719

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00282

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000560

Hom.:

Bravo

AF:

0.000427

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial hemophagocytic lymphohistiocytosis 3 (2)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.72

(source)

DANN

Benign

0.84

PhyloP100

-7.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over