rs75853379

Positions:

• chr17-75835513-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_199242.3(UNC13D):​c.1744C>T​(p.Leu582=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,606,538 control chromosomes in the GnomAD database, including 299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (134 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (165 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.41

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 17-75835513-G-A is Benign according to our data. Variant chr17-75835513-G-A is described in ClinVar as [Benign]. Clinvar id is 263218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.1744C>T	p.Leu582=	synonymous_variant	20/32	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.1744C>T	p.Leu582=	synonymous_variant	20/32	1	NM_199242.3	ENSP00000207549	P1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3773 AN: 152184 Hom.: 133 Cov.: 33

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0208

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0144 AC: 3339 AN: 232320 Hom.: 85 AF XY: 0.0122 AC XY: 1533 AN XY: 126162

Gnomad AFR exome AF: 0.0815

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.00207

Gnomad EAS exome AF: 0.0270

Gnomad SAS exome AF: 0.0132

Gnomad FIN exome AF: 0.000674

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00942

GnomAD4 exome AF: 0.00491 AC: 7147 AN: 1454236 Hom.: 165 Cov.: 33 AF XY: 0.00482 AC XY: 3487 AN XY: 722852

Gnomad4 AFR exome AF: 0.0759

Gnomad4 AMR exome AF: 0.0321

Gnomad4 ASJ exome AF: 0.00258

Gnomad4 EAS exome AF: 0.0175

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.000919

Gnomad4 NFE exome AF: 0.000593

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0249 AC: 3789 AN: 152302 Hom.: 134 Cov.: 33 AF XY: 0.0245 AC XY: 1823 AN XY: 74486

Gnomad4 AFR AF: 0.0759

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0253

Gnomad4 SAS AF: 0.0147

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.0217

Alfa AF: 0.0116 Hom.: 35

Bravo AF: 0.0295

Asia WGS AF: 0.0240 AC: 82 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.6
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs75853379; hg19: chr17-73831594; COSMIC: COSV104392665; COSMIC: COSV104392665;