rs754621494

Variant names:

• chr17-75835410-T-C
• rs754621494
• NM_199242.3:c.1847A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-75835410-T-C
• chr17-75835410-T-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_199242.3(UNC13D):​c.1847A>G​(p.Glu616Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,459,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: UNC13D NM_199242.3 missense, splice_region
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.23
• Publications: 7 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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-75835410-T-C is Pathogenic according to our data. Variant chr17-75835410-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 445606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1847A>G	p.Glu616Gly	missense splice_region	Exon 20 of 32	NP_954712.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.1847A>G	p.Glu616Gly	missense splice_region	Exon 20 of 32	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.1847A>G	p.Glu616Gly	missense splice_region	Exon 20 of 33	ENSP00000388093.1
	UNC13D	ENST00000699510.1		c.782A>G	p.Glu261Gly	missense splice_region	Exon 8 of 20	ENSP00000514405.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459368 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 725906

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5376

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111554

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.11
Sift	Benign	0.17	T
Sift4G	Uncertain	0.016	D
Polyphen		0.12	B
Vest4		0.30
MutPred		0.37		Loss of solvent accessibility (P = 0.0299)
MVP		0.64
MPC		0.13
ClinPred		0.38	T
GERP RS		-0.47
Varity_R		0.080
gMVP		0.16
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: 26
DS_DL_spliceai		0.54		Position offset: -1

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

Other links and lift over

dbSNP: rs754621494; hg19: chr17-73831491;