17-75828796-C-T

Variant names:

• chr17-75828796-C-T
• rs758781229
• NM_199242.3:c.3142G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_199242.3(UNC13D):​c.3142G>A​(p.Ala1048Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,544,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.538
• 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_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02714479).

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.3142G>A	p.Ala1048Thr	missense	Exon 31 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.3142G>A	p.Ala1048Thr	missense	Exon 31 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.3142G>A	p.Ala1048Thr	missense	Exon 31 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.3142G>A	p.Ala1048Thr	missense	Exon 32 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000754 AC: 11 AN: 145854 AF XY: 0.0000887

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000874

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000729

Gnomad OTH exome AF: 0.000236

GnomAD4 exome AF: 0.0000467 AC: 65 AN: 1392478 Hom.: 0 Cov.: 31 AF XY: 0.0000583 AC XY: 40 AN XY: 686510

African (AFR) AF: 0.00 AC: 0 AN: 31860

American (AMR) AF: 0.0000279 AC: 1 AN: 35828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25070

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36062

South Asian (SAS) AF: 0.000176 AC: 14 AN: 79482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43638

Middle Eastern (MID) AF: 0.000658 AC: 3 AN: 4562

European-Non Finnish (NFE) AF: 0.0000343 AC: 37 AN: 1078248

Other (OTH) AF: 0.000156 AC: 9 AN: 57728

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000266 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.54
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.081
Sift	Benign	0.056	T
Sift4G	Benign	0.17	T
Polyphen		0.41	B
Vest4		0.14
MutPred		0.18		Gain of phosphorylation at A1048 (P = 0.0134)
MVP		0.45
MPC		0.094
ClinPred		0.071	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.42
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs758781229; hg19: chr17-73824877;