Variant 17-75830364-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_199242.3(UNC13D):c.2828A>G(p.Asn943Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000533 in 1,593,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

UNC13D
NM_199242.3 missense, splice_region

Scores

Splicing: ADA: 0.1588

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.58

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016261786).

BP6

Variant 17-75830364-T-C is Benign according to our data. Variant chr17-75830364-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 533103.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75830364-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00152 (232/152318) while in subpopulation AFR AF= 0.00481 (200/41568). AF 95% confidence interval is 0.00426. There are 0 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.2828A>G	p.Asn943Ser	missense_variant, splice_region_variant	29/32	ENST00000207549.9	NP_954712.1	Q70J99-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9 link	c.2828A>G	p.Asn943Ser	missense_variant, splice_region_variant	29/32	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

227

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00468

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000528

AC:

114

AN:

215958

Hom.:

AF XY:

0.000507

AC XY:

AN XY:

116440

show subpopulations

Gnomad AFR exome

AF:

0.00542

Gnomad AMR exome

AF:

0.000228

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000742

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000313

Gnomad OTH exome

AF:

0.000558

GnomAD4 exome

AF:

0.000428

AC:

617

AN:

1441320

Hom.:

Cov.:

AF XY:

0.000401

AC XY:

287

AN XY:

714998

show subpopulations

Gnomad4 AFR exome

AF:

0.00443

Gnomad4 AMR exome

AF:

0.000289

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0000723

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.000362

Gnomad4 OTH exome

AF:

0.000823

GnomAD4 genome

AF:

0.00152

AC:

232

AN:

152318

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

106

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00481

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000630

Hom.:

Bravo

AF:

0.00173

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00569

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000565

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

2.0

M;M

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0040

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.91

P;.

Vest4

0.63

MVP

0.81

MPC

0.43

ClinPred

0.051

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.48

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.16

dbscSNV1_RF

Benign

0.39

SpliceAI score (max)

0.040

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