chr17-75843245-C-T

Position:

chr17-75843245-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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:4

Conservation

PhyloP100: 1.87

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 links:

UNC13D (HGNC:):

UNC13D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 263219.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}. Variant chr17-75843245-C-T is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13D	NM_199242.3 linkuse as main transcript	c.175G>A	p.Ala59Thr	missense_variant	3/32	ENST00000207549.9	NP_954712.1	Q70J99-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9 linkuse as main transcript	c.175G>A	p.Ala59Thr	missense_variant	3/32	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

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

GnomAD3 exomes

AF:

0.0159

AC:

3919

AN:

246844

Hom.:

AF XY:

0.0171

AC XY:

2298

AN XY:

134276

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 SAS exome

AF:

0.0209

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

Gnomad4 AFR exome

AF:

0.0168

Gnomad4 AMR exome

AF:

0.0152

Gnomad4 ASJ exome

AF:

0.0625

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0206

Gnomad4 FIN exome

AF:

0.00150

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.0204

GnomAD4 genome

AF:

0.0145

AC:

2204

AN:

152110

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1040

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0129

Gnomad4 AMR

AF:

0.0164

Gnomad4 ASJ

AF:

0.0735

Gnomad4 EAS

AF:

0.000582

Gnomad4 SAS

AF:

0.0224

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.0136

Gnomad4 OTH

AF:

0.0294

Alfa

AF:

0.0174

Hom.:

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.;T;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.73

T;T;T;T;T

MetaRNN

Benign

0.0045

T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.7

L;L;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

N;N;.;.;.

REVEL

Benign

0.075

Sift

Benign

0.041

D;D;.;.;.

Sift4G

Benign

0.35

T;T;T;T;.

Polyphen

0.0050

B;.;.;.;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over