17-75836642-T-C

Variant names:

• chr17-75836642-T-C
• rs117221419
• NM_199242.3:c.1228A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_199242.3(UNC13D):​c.1228A>G​(p.Ile410Val) 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. 15/22 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. I410L) 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: 1.12
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_199242.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16850096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.1228A>G	p.Ile410Val	missense_variant	Exon 14 of 32	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.1228A>G	p.Ile410Val	missense_variant	Exon 14 of 32	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000506 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Uncertain	0.97
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.46	N;N
PhyloP100		1.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.10
Sift	Benign	0.29	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.20	B;B
Vest4		0.28
MutPred		0.35		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.64
MPC		0.081
ClinPred		0.38	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.083

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: rs117221419; hg19: chr17-73832723;