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, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

Sel.	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	Q70J99-1

Ensembl Transcripts

Sel.	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	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.118-308C>T		intron	N/A	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.118-308C>T		intron	N/A	ENSP00000538159.1

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Familial hemophagocytic lymphohistiocytosis 3 (7)
1	-	-	Familial hemophagocytic lymphohistiocytosis (1)
1	-	-	not provided (1)

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;