17-75834646-T-G

Variant names:

• chr17-75834646-T-G
• rs777159773
• NM_199242.3:c.2063A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_199242.3(UNC13D):​c.2063A>C​(p.Gln688Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q688R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3713852).

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.2063A>C	p.Gln688Pro	missense	Exon 22 of 32	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.2063A>C	p.Gln688Pro	missense	Exon 22 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.2063A>C	p.Gln688Pro	missense	Exon 22 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.2063A>C	p.Gln688Pro	missense	Exon 23 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hemophagocytic lymphohistiocytosis 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.096
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.22
Sift	Benign	0.36	T
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.56
MutPred		0.29		Gain of glycosylation at Q688 (P = 0.0185)
MVP		0.81
MPC		0.12
ClinPred		0.38	T
GERP RS		4.9
Varity_R		0.17
gMVP		0.27

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: rs777159773; hg19: chr17-73830727;