rs3744007

chr17-75843056-G-Achr17-75843056-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_199242.3(UNC13D):c.279C>T(p.Pro93=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,609,490 control chromosomes in the GnomAD database, including 2,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P93P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (343 hom., cov: 32)
  • Exomes 𝑓: 0.031 (2368 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.26

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=-0.85).
• BP6: Variant 17-75843056-G-A is Benign according to our data. Variant chr17-75843056-G-A is described in ClinVar as [Benign]. Clinvar id is 263235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75843056-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.279C>T	p.Pro93=	synonymous_variant	4/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.279C>T	p.Pro93=	synonymous_variant	4/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6843 AN: 151958 Hom.: 343 Cov.: 32

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0338

Gnomad ASJ AF: 0.0755

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.0519

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0555

GnomAD3 exomes AF: 0.0495 AC: 12144 AN: 245370 Hom.: 885 AF XY: 0.0487 AC XY: 6526 AN XY: 133878

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.0234

Gnomad ASJ exome AF: 0.0665

Gnomad EAS exome AF: 0.282

Gnomad SAS exome AF: 0.0444

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.0238

Gnomad OTH exome AF: 0.0417

GnomAD4 exome AF: 0.0312 AC: 45465 AN: 1457414 Hom.: 2368 Cov.: 37 AF XY: 0.0319 AC XY: 23137 AN XY: 725090

Gnomad4 AFR exome AF: 0.0670

Gnomad4 AMR exome AF: 0.0236

Gnomad4 ASJ exome AF: 0.0660

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.0439

Gnomad4 FIN exome AF: 0.0169

Gnomad4 NFE exome AF: 0.0190

Gnomad4 OTH exome AF: 0.0447

GnomAD4 genome AF: 0.0449 AC: 6834 AN: 152076 Hom.: 343 Cov.: 32 AF XY: 0.0465 AC XY: 3453 AN XY: 74330

Gnomad4 AFR AF: 0.0640

Gnomad4 AMR AF: 0.0338

Gnomad4 ASJ AF: 0.0755

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.0520

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.0204

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0231 Hom.: 44

Bravo AF: 0.0495

Asia WGS AF: 0.128 AC: 443 AN: 3478

EpiCase AF: 0.0274

EpiControl AF: 0.0309

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-0.85
Cadd	Benign	0.057
Dann	Benign	0.70
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: rs3744007; hg19: chr17-73839137; COSMIC: COSV52884658; COSMIC: COSV52884658;