rs2290770

chr17-75834935-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.1977C>T(p.Thr659=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,614,026 control chromosomes in the GnomAD database, including 2,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (259 hom., cov: 33)
  • Exomes 𝑓: 0.012 (1788 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00

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=-0.36).
• BP6: Variant 17-75834935-G-A is Benign according to our data. Variant chr17-75834935-G-A is described in ClinVar as [Benign]. Clinvar id is 263220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.1977C>T	p.Thr659=	synonymous_variant	21/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.1977C>T	p.Thr659=	synonymous_variant	21/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4159 AN: 152126 Hom.: 259 Cov.: 33

Gnomad AFR AF: 0.0511

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.0216

GnomAD3 exomes AF: 0.0302 AC: 7581 AN: 251390 Hom.: 803 AF XY: 0.0282 AC XY: 3827 AN XY: 135904

Gnomad AFR exome AF: 0.0494

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.285

Gnomad SAS exome AF: 0.0218

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0124 AC: 18167 AN: 1461782 Hom.: 1788 Cov.: 34 AF XY: 0.0126 AC XY: 9143 AN XY: 727186

Gnomad4 AFR exome AF: 0.0505

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.0212

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0273 AC: 4153 AN: 152244 Hom.: 259 Cov.: 33 AF XY: 0.0295 AC XY: 2195 AN XY: 74432

Gnomad4 AFR AF: 0.0509

Gnomad4 AMR AF: 0.00883

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.0247

Gnomad4 FIN AF: 0.0170

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.00660 Hom.: 47

Bravo AF: 0.0301

Asia WGS AF: 0.118 AC: 409 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00184

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	6.4
Dann	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs2290770; hg19: chr17-73831016; COSMIC: COSV52883519; COSMIC: COSV52883519;