rs9904366

Positions:

• chr17-75843245-C-A
• chr17-75843245-C-G
• chr17-75843245-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_199242.3(UNC13D):​c.175G>T​(p.Ala59Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A59T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2812813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.175G>T	p.Ala59Ser	missense_variant	3/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.175G>T	p.Ala59Ser	missense_variant	3/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.;T;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;T;T;D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.
MutationTaster	Benign	0.79	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N;N;.;.;.
REVEL	Benign	0.071
Sift	Uncertain	0.0060	D;D;.;.;.
Sift4G	Benign	0.094	T;T;T;T;.
Polyphen		0.26	B;.;.;.;.
Vest4		0.34
MutPred		0.30		Gain of disorder (P = 0.0455);Gain of disorder (P = 0.0455);.;.;Gain of disorder (P = 0.0455);
MVP		0.67
MPC		0.15
ClinPred		0.89	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs9904366; hg19: chr17-73839326;