rs959968589

Variant names:

• chr17-75843827-G-A
• rs959968589
• NM_199242.3:c.118-308C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-75843827-G-A
• chr17-75843827-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_199242.3(UNC13D):​c.118-308C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,376,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 0.359
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 17-75843827-G-A is Pathogenic according to our data. Variant chr17-75843827-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 533095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.

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.118-308C>T		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.118-308C>T		intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000588774.2	TSL:3	n.597C>T		non_coding_transcript_exon	Exon 2 of 3
	UNC13D	ENST00000412096.6	TSL:2	c.118-308C>T		intron	N/A	ENSP00000388093.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000194 AC: 237 AN: 1224488 Hom.: 0 Cov.: 32 AF XY: 0.000193 AC XY: 114 AN XY: 590014

African (AFR) AF: 0.00 AC: 0 AN: 27138

American (AMR) AF: 0.00 AC: 0 AN: 17410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17308

East Asian (EAS) AF: 0.0000990 AC: 3 AN: 30318

South Asian (SAS) AF: 0.00 AC: 0 AN: 59356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3300

European-Non Finnish (NFE) AF: 0.000234 AC: 233 AN: 994962

Other (OTH) AF: 0.0000200 AC: 1 AN: 50102

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74344

African (AFR) AF: 0.000121 AC: 5 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000818 Hom.: 0

Bravo AF: 0.000132

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Pathogenic:6 Other:1

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 1 of the UNC13D gene. It does not directly change the encoded amino acid sequence of the UNC13D protein. This variant is present in population databases (no rsID available, gnomAD 0.05%). This variant has been observed in individuals with familial hemophagocytic lymphohistiocytosis (FHL), and it has been described as a recurrent FHL-causing variant in Northern European and Korean populations (PMID: 21931115, 23180437, 24470399, 24935083, 25553300, 25573973). ClinVar contains an entry for this variant (Variation ID: 533095). Studies have shown that this variant alters UNC13D gene expression (PMID: 21931115, 24842371). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic.

Jan 03, 2023

Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 10, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.019%). Predicted Consequence/Location: Intron variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 24842371). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 23180437). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000533095 /PMID: 21931115 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Aug 29, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Disruption of lymphocyte-specific enhancer [Meeths et al 2011]. Frequent cause of disease in persons of northern European background [Meeths et al 2011] & Koreans [Seo et al 2013]

Familial hemophagocytic lymphohistiocytosis Pathogenic:1

May 26, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: UNC13D c.118-308C>T is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. Sequence analysis of patient samples confirmed these predictions, revealing correctly spliced products (Meeths_2011). The variant allele was found at a frequency of 0.00019 in 150968 control chromosomes (gnomAD v3.1.2). This frequency is not higher than expected for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis (0.00019 vs 0.0027), allowing no conclusion about variant significance. c.118-308C>T has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Meeths_2011, Seo_2013). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant abolished an ELF1-binding site that is necessary for the recruitment of STAT4 and BRG1, diminishing active histone modifications at the locus and impaired UNC13D transcription in lymphocytes (Meeths_2011, Cichocki_2014). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

not provided Pathogenic:1

Jul 21, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect as this variant disrupts an ELF1 transcription factor binding site and has a negative regulatory effect on transcription (PMID: 24842371); In silico analysis suggests that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 24935083, 29596912, 32582217, 25252047, 21931115, 25573973, 29665027, 24470399, 25553300, 32542393, 35773766, 33258288, 33365035, 32378134, 34170459, 23180437, 24842371, 34964741, 37851074, 38747707)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.99
PhyloP100		0.36
PromoterAI		-0.89	Under-expression
Mutation Taster		=35/65	disease causing (ClinVar)

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: rs959968589; hg19: chr17-73839908;