rs118049905

chr17-75830086-G-Achr17-75830086-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_199242.3(UNC13D):c.2896C>T(p.Arg966Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,580,010 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R966G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (28 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.63

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009559631).
• BP6: Variant 17-75830086-G-A is Benign according to our data. Variant chr17-75830086-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263237.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr17-75830086-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00373 (568/152280) while in subpopulation NFE AF= 0.00609 (414/68012). AF 95% confidence interval is 0.0056. There are 1 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.2896C>T	p.Arg966Trp	missense_variant	30/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.2896C>T	p.Arg966Trp	missense_variant	30/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00441 AC: 852 AN: 193394 Hom.: 2 AF XY: 0.00448 AC XY: 464 AN XY: 103618

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.00426

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000800

Gnomad FIN exome AF: 0.00486

Gnomad NFE exome AF: 0.00763

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00599 AC: 8558 AN: 1427730 Hom.: 28 Cov.: 31 AF XY: 0.00582 AC XY: 4111 AN XY: 706932

Gnomad4 AFR exome AF: 0.000851

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00485

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00538

Gnomad4 NFE exome AF: 0.00711

Gnomad4 OTH exome AF: 0.00436

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74458

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00609

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00543 Hom.: 1

Bravo AF: 0.00326

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00710 AC: 61

ExAC AF: 0.00438 AC: 525

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in the heterozygous state without a second UNC13D variant in individuals with familial hemophagocytic lymphohistiocytosis in the literature (Zhang et al., 2014); these individuals also had a single heterozygous variant in the PRF1 gene suggesting possible digenic inheritance; Identified in the heterozygous state in patients with suspected bleeding disorders in published literature, although one of the patients also had a variant in the RUNX1 gene (Ferrari et al., 2018); This variant is associated with the following publications: (PMID: 24916509, 28399723) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	UNC13D: BS2 -

Familial hemophagocytic lymphohistiocytosis 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0096	T;T
MetaSVM	Uncertain	0.040	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.69
MVP		0.91
MPC		0.51
ClinPred		0.028	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.39
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs118049905; hg19: chr17-73826167; COSMIC: COSV52885885; COSMIC: COSV52885885;