rs55661958

chr17-75840065-G-Achr17-75840065-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_199242.3(UNC13D):c.904C>T(p.Leu302Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,592 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L302L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (29 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.05

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002488196).
• BP6: Variant 17-75840065-G-A is Benign according to our data. Variant chr17-75840065-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 325269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75840065-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0098 (1492/152310) while in subpopulation AFR AF= 0.0339 (1408/41564). AF 95% confidence interval is 0.0324. There are 24 homozygotes in gnomad4. There are 720 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.904C>T	p.Leu302Phe	missense_variant	11/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.904C>T	p.Leu302Phe	missense_variant	11/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.00976 AC: 1485 AN: 152192 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00271 AC: 677 AN: 249460 Hom.: 7 AF XY: 0.00213 AC XY: 288 AN XY: 135290

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.000701

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00108 AC: 1573 AN: 1461282 Hom.: 29 Cov.: 33 AF XY: 0.000896 AC XY: 651 AN XY: 726966

Gnomad4 AFR exome AF: 0.0358

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000800

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.00980 AC: 1492 AN: 152310 Hom.: 24 Cov.: 32 AF XY: 0.00967 AC XY: 720 AN XY: 74478

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00248 Hom.: 7

Bravo AF: 0.0118

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00325 AC: 394

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:3

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	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 05, 2022	- -

UNC13D-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	17
Dann	Benign	0.89
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.28	N;N;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.39	N;N;.
REVEL	Benign	0.062
Sift	Benign	0.58	T;T;.
Sift4G	Benign	0.69	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.083
MVP		0.60
MPC		0.11
ClinPred		0.00071	T
GERP RS		3.4
Varity_R		0.039
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs55661958; hg19: chr17-73836146; COSMIC: COSV104392535; COSMIC: COSV104392535;