rs3744007

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_199242.3(UNC13D):c.279C>T(p.Pro93Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,609,490 control chromosomes in the GnomAD database, including 2,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P93P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.045 ( 343 hom., cov: 32)

Exomes 𝑓: 0.031 ( 2368 hom. )

Consequence

UNC13D
NM_199242.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -3.26

Publications

16 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Laboratory for Molecular Medicine
hereditary hemophagocytic lymphohistiocytosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

UNC13D links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_199242.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 17-75843056-G-A is Benign according to our data. Variant chr17-75843056-G-A is described in ClinVar as Benign. ClinVar VariationId is 263235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 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.279C>T	p.Pro93Pro	synonymous	Exon 4 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.279C>T	p.Pro93Pro	synonymous	Exon 4 of 32	ENSP00000207549.3	Q70J99-1
UNC13D	ENST00000412096.6	TSL:2	c.279C>T	p.Pro93Pro	synonymous	Exon 4 of 33	ENSP00000388093.1	Q70J99-3
UNC13D	ENST00000868100.1		c.279C>T	p.Pro93Pro	synonymous	Exon 5 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes

AF:

0.0450

AC:

6843

AN:

151958

Hom.:

343

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0642

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0338

Gnomad ASJ

AF:

0.0755

Gnomad EAS

AF:

0.273

Gnomad SAS

AF:

0.0519

Gnomad FIN

AF:

0.0184

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0204

Gnomad OTH

AF:

0.0555

GnomAD2 exomes

AF:

0.0495

AC:

12144

AN:

245370

AF XY:

0.0487

show subpopulations

Gnomad AFR exome

AF:

0.0629

Gnomad AMR exome

AF:

0.0234

Gnomad ASJ exome

AF:

0.0665

Gnomad EAS exome

AF:

0.282

Gnomad FIN exome

AF:

0.0162

Gnomad NFE exome

AF:

0.0238

Gnomad OTH exome

AF:

0.0417

GnomAD4 exome

AF:

0.0312

AC:

45465

AN:

1457414

Hom.:

2368

Cov.:

AF XY:

0.0319

AC XY:

23137

AN XY:

725090

show subpopulations

African (AFR)

AF:

0.0670

AC:

2238

AN:

33406

American (AMR)

AF:

0.0236

AC:

1056

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.0660

AC:

1719

AN:

26038

East Asian (EAS)

AF:

0.283

AC:

11210

AN:

39634

South Asian (SAS)

AF:

0.0439

AC:

3783

AN:

86244

European-Finnish (FIN)

AF:

0.0169

AC:

854

AN:

50578

Middle Eastern (MID)

AF:

0.149

AC:

842

AN:

5654

European-Non Finnish (NFE)

AF:

0.0190

AC:

21070

AN:

1110974

Other (OTH)

AF:

0.0447

AC:

2693

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2784

5569

8353

11138

13922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

972

1944

2916

3888

4860

<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:

0.0449

AC:

6834

AN:

152076

Hom.:

343

Cov.:

AF XY:

0.0465

AC XY:

3453

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0640

AC:

2657

AN:

41492

American (AMR)

AF:

0.0338

AC:

517

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0755

AC:

262

AN:

3470

East Asian (EAS)

AF:

0.272

AC:

1394

AN:

5122

South Asian (SAS)

AF:

0.0520

AC:

250

AN:

4812

European-Finnish (FIN)

AF:

0.0184

AC:

195

AN:

10612

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0204

AC:

1387

AN:

67946

Other (OTH)

AF:

0.0549

AC:

116

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

316

632

949

1265

1581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0245

Hom.:

Bravo

AF:

0.0495

Asia WGS

AF:

0.128

AC:

443

AN:

3478

EpiCase

AF:

0.0274

EpiControl

AF:

0.0309

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial hemophagocytic lymphohistiocytosis 3 (3)

not specified (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.057

(source)

DANN

Benign

0.70

PhyloP100

-3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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