17-75831124-T-C

Variant names:

• chr17-75831124-T-C
• rs1135688
• NM_199242.3:c.2599A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199242.3(UNC13D):​c.2599A>G​(p.Lys867Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,613,702 control chromosomes in the GnomAD database, including 107,159 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (20270 hom., cov: 33)
  • Exomes 𝑓: 0.33 (86889 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 1.07
• Publications: 48 publications found

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, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302174 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.4924445E-7).
• BP6: Variant 17-75831124-T-C is Benign according to our data. Variant chr17-75831124-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.2599A>G	p.Lys867Glu	missense_variant	Exon 27 of 32	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.2599A>G	p.Lys867Glu	missense_variant	Exon 27 of 32	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70060 AN: 152032 Hom.: 20220 Cov.: 33

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.451

GnomAD2 exomes AF: 0.353 AC: 88391 AN: 250424 AF XY: 0.350

Gnomad AFR exome AF: 0.844

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.427

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.320

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.332 AC: 485186 AN: 1461550 Hom.: 86889 Cov.: 54 AF XY: 0.332 AC XY: 241665 AN XY: 727052

African (AFR) AF: 0.846 AC: 28314 AN: 33480

American (AMR) AF: 0.255 AC: 11401 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 11064 AN: 26136

East Asian (EAS) AF: 0.439 AC: 17441 AN: 39696

South Asian (SAS) AF: 0.357 AC: 30772 AN: 86252

European-Finnish (FIN) AF: 0.232 AC: 12326 AN: 53172

Middle Eastern (MID) AF: 0.495 AC: 2858 AN: 5768

European-Non Finnish (NFE) AF: 0.314 AC: 348807 AN: 1111954

Other (OTH) AF: 0.368 AC: 22203 AN: 60382

GnomAD4 genome AF: 0.461 AC: 70162 AN: 152152 Hom.: 20270 Cov.: 33 AF XY: 0.452 AC XY: 33627 AN XY: 74374

African (AFR) AF: 0.826 AC: 34313 AN: 41542

American (AMR) AF: 0.319 AC: 4877 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1496 AN: 3470

East Asian (EAS) AF: 0.427 AC: 2210 AN: 5170

South Asian (SAS) AF: 0.343 AC: 1651 AN: 4820

European-Finnish (FIN) AF: 0.228 AC: 2417 AN: 10588

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21869 AN: 67966

Other (OTH) AF: 0.455 AC: 958 AN: 2106

Alfa AF: 0.391 Hom.: 23880

Bravo AF: 0.488

TwinsUK AF: 0.312 AC: 1157

ALSPAC AF: 0.317 AC: 1222

ESP6500AA AF: 0.820 AC: 3612

ESP6500EA AF: 0.326 AC: 2800

ExAC AF: 0.365 AC: 44265

Asia WGS AF: 0.418 AC: 1453 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied by a panel of primary immunodeficiencies. Number of patients: 39. Only high quality variants are reported. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Familial hemophagocytic lymphohistiocytosis 3 Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.7
DANN	Benign	0.16
DEOGEN2	Benign	0.047	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.096	T;T
MetaRNN	Benign	9.5e-7	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.5	N;N
PhyloP100		1.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.8	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.023
MPC		0.14
ClinPred		0.00042	T
GERP RS		3.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.096
gMVP		0.084
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1135688; hg19: chr17-73827205; COSMIC: COSV52884077; COSMIC: COSV52884077;