rs150861045

chr17-75834657-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_199242.3(UNC13D):c.2052C>G(p.Leu684=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,778 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (9 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.685

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 17-75834657-G-C is Benign according to our data. Variant chr17-75834657-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 263223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75834657-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.685 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00088 (134/152302) while in subpopulation SAS AF= 0.00477 (23/4818). AF 95% confidence interval is 0.00326. There are 0 homozygotes in gnomad4. There are 65 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.2052C>G	p.Leu684=	synonymous_variant	22/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.2052C>G	p.Leu684=	synonymous_variant	22/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00208 AC: 520 AN: 250278 Hom.: 2 AF XY: 0.00243 AC XY: 330 AN XY: 135676

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00937

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00715

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00123 AC: 1804 AN: 1461476 Hom.: 9 Cov.: 33 AF XY: 0.00148 AC XY: 1078 AN XY: 727020

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00937

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00738

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000629

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000873 AC XY: 65 AN XY: 74468

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00210 Hom.: 0

Bravo AF: 0.000960

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely 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	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

UNC13D: BP4, BP7 -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	4.9
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs150861045; hg19: chr17-73830738; COSMIC: COSV104392698; COSMIC: COSV104392698;