rs140758914

Variant names:

• chr17-75840005-A-C
• rs140758914
• NM_199242.3:c.951+13T>G

Your query was ambiguous. Multiple possible variants found:

• chr17-75840005-A-C
• chr17-75840005-A-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.951+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,498 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (51 hom., cov: 32)
  • Exomes 𝑓: 0.018 (456 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.323
• Publications: 2 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=-0.83).
• BP6: Variant 17-75840005-A-C is Benign according to our data. Variant chr17-75840005-A-C is described in ClinVar as Benign. ClinVar VariationId is 263248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.951+13T>G		intron_variant	Intron 11 of 31	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.951+13T>G		intron_variant	Intron 11 of 31	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2582 AN: 152230 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0744

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0187 AC: 4654 AN: 249368 AF XY: 0.0202

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0637

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.00136

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0263

GnomAD4 exome AF: 0.0183 AC: 26705 AN: 1461150 Hom.: 456 Cov.: 33 AF XY: 0.0190 AC XY: 13802 AN XY: 726898

African (AFR) AF: 0.0159 AC: 531 AN: 33474

American (AMR) AF: 0.0177 AC: 793 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 1638 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0250 AC: 2159 AN: 86248

European-Finnish (FIN) AF: 0.00193 AC: 102 AN: 52932

Middle Eastern (MID) AF: 0.133 AC: 760 AN: 5730

European-Non Finnish (NFE) AF: 0.0173 AC: 19268 AN: 1111890

Other (OTH) AF: 0.0241 AC: 1453 AN: 60374

GnomAD4 genome AF: 0.0169 AC: 2578 AN: 152348 Hom.: 51 Cov.: 32 AF XY: 0.0163 AC XY: 1215 AN XY: 74504

African (AFR) AF: 0.0126 AC: 525 AN: 41590

American (AMR) AF: 0.0195 AC: 299 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0744 AC: 258 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0271 AC: 131 AN: 4828

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10624

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1226 AN: 68022

Other (OTH) AF: 0.0327 AC: 69 AN: 2112

Alfa AF: 0.0189 Hom.: 63

Bravo AF: 0.0186

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.4
DANN	Benign	0.46
PhyloP100		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	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: rs140758914; hg19: chr17-73836086; COSMIC: COSV104392536;