17-75843285-C-T

Variant names:

• chr17-75843285-C-T
• rs3744009
• NM_199242.3:c.154-19G>A

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.154-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,602,580 control chromosomes in the GnomAD database, including 55,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8145 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47458 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.442
• Publications: 10 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-75843285-C-T is Benign according to our data. Variant chr17-75843285-C-T is described in ClinVar as Benign. ClinVar VariationId is 263214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	NM_199242.3	MANE Select	c.154-19G>A		intron	N/A	NP_954712.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.154-19G>A		intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.154-19G>A		intron	N/A	ENSP00000388093.1
	UNC13D	ENST00000592386.6	TSL:5	c.154-37G>A		intron	N/A	ENSP00000466826.2

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46174 AN: 151894 Hom.: 8116 Cov.: 32

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.301

GnomAD2 exomes AF: 0.244 AC: 58503 AN: 239842 AF XY: 0.242

Gnomad AFR exome AF: 0.492

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.251 AC: 363713 AN: 1450568 Hom.: 47458 Cov.: 36 AF XY: 0.249 AC XY: 180061 AN XY: 721984

African (AFR) AF: 0.486 AC: 16261 AN: 33448

American (AMR) AF: 0.202 AC: 9008 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 7812 AN: 26126

East Asian (EAS) AF: 0.108 AC: 4268 AN: 39664

South Asian (SAS) AF: 0.220 AC: 18982 AN: 86182

European-Finnish (FIN) AF: 0.185 AC: 8021 AN: 43408

Middle Eastern (MID) AF: 0.261 AC: 1444 AN: 5540

European-Non Finnish (NFE) AF: 0.254 AC: 282256 AN: 1111378

Other (OTH) AF: 0.260 AC: 15661 AN: 60242

GnomAD4 genome AF: 0.304 AC: 46247 AN: 152012 Hom.: 8145 Cov.: 32 AF XY: 0.295 AC XY: 21941 AN XY: 74312

African (AFR) AF: 0.480 AC: 19877 AN: 41414

American (AMR) AF: 0.227 AC: 3472 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1011 AN: 3470

East Asian (EAS) AF: 0.116 AC: 598 AN: 5170

South Asian (SAS) AF: 0.208 AC: 1001 AN: 4820

European-Finnish (FIN) AF: 0.180 AC: 1904 AN: 10584

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17433 AN: 67956

Other (OTH) AF: 0.308 AC: 652 AN: 2114

Alfa AF: 0.206 Hom.: 651

Bravo AF: 0.318

Asia WGS AF: 0.214 AC: 745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Familial hemophagocytic lymphohistiocytosis 3 Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.91
PhyloP100		0.44
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3744009; hg19: chr17-73839366; COSMIC: COSV52888511; COSMIC: COSV52888511;