17-75834443-C-T

Variant names:

• chr17-75834443-C-T
• rs747390615
• NM_199242.3:c.2180G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_199242.3(UNC13D):​c.2180G>A​(p.Arg727Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,565,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.471

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
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000269 (380/1413408) while in subpopulation MID AF= 0.00158 (9/5694). AF 95% confidence interval is 0.000902. There are 0 homozygotes in gnomad4_exome. There are 205 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.2180G>A	p.Arg727Gln	missense_variant	Exon 23 of 32	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.2180G>A	p.Arg727Gln	missense_variant	Exon 23 of 32	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000439 AC: 76 AN: 173178 Hom.: 1 AF XY: 0.000424 AC XY: 40 AN XY: 94334

Gnomad AFR exome AF: 0.000101

Gnomad AMR exome AF: 0.000671

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00145

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.000211

GnomAD4 exome AF: 0.000269 AC: 380 AN: 1413408 Hom.: 0 Cov.: 33 AF XY: 0.000293 AC XY: 205 AN XY: 700226

Gnomad4 AFR exome AF: 0.000215

Gnomad4 AMR exome AF: 0.000603

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.000121

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.000391

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74508

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000286 AC: 34

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: UNC13D c.2180G>A (p.Arg727Gln) results in a conservative amino acid change located in the MUN domain (IPR010439) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 173178 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis (0.00044 vs 0.0027), allowing no conclusion about variant significance. c.2180G>A has been reported in the literature in either the compound heterozygous or heterozygous state in individuals affected with Familial Hemophagocytic Lymphohistiocytosis or other immune dysregulation disorders, without strong evidence for causality (e.g. Sieni_2011, Batlle-Maso_2020, Xinh_2021, Allain_2023) . These reports do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. At least one publication reports experimental evidence evaluating an impact on protein function (Shibata_2018). These results suggested the variant may have mild to moderately reduced stability, but showed no damaging effect on degranulation and cytolytic activity in vitro and was capable of restoring the degranulation and cytolytic activity of a familial hemophagocytic lymphohistiocytosis cell line to levels comparable with cells transfected with the WT protein. The following publications have been ascertained in the context of this evaluation (PMID: 36155879, 32222431, 29549174, 21248318, 34339548). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either uncertain significance or likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Autoinflammatory syndrome Uncertain:1

Feb 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hemophagocytic lymphohistiocytosis 3 Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.77	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.11
Sift	Benign	0.24	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.53	P;P
Vest4		0.22
MVP		0.61
MPC		0.14
ClinPred		0.022	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs747390615; hg19: chr17-73830524;