rs75366116

chr17-75835872-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199242.3(UNC13D):c.1579C>T(p.Arg527Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,614,156 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R527Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (66 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (60 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.919

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=0.00578171).
• BP6: Variant 17-75835872-G-A is Benign according to our data. Variant chr17-75835872-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75835872-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.1579C>T	p.Arg527Trp	missense_variant	18/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.1579C>T	p.Arg527Trp	missense_variant	18/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2318 AN: 152212 Hom.: 66 Cov.: 33

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00395 AC: 992 AN: 251354 Hom.: 20 AF XY: 0.00302 AC XY: 410 AN XY: 135858

Gnomad AFR exome AF: 0.0563

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00161 AC: 2355 AN: 1461826 Hom.: 60 Cov.: 35 AF XY: 0.00136 AC XY: 990 AN XY: 727214

Gnomad4 AFR exome AF: 0.0576

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000139

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.0152 AC: 2321 AN: 152330 Hom.: 66 Cov.: 33 AF XY: 0.0149 AC XY: 1112 AN XY: 74488

Gnomad4 AFR AF: 0.0533

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00285 Hom.: 13

Bravo AF: 0.0170

ESP6500AA AF: 0.0524 AC: 231

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00524 AC: 636

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 10, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Dec 22, 2015

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-4.7	D;D;.
REVEL	Benign	0.24
Sift	Uncertain	0.024	D;D;.
Sift4G	Uncertain	0.022	D;D;.
Polyphen		0.90	P;D;.
Vest4		0.24
MVP		0.83
MPC		0.10
ClinPred		0.030	T
GERP RS		0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75366116; hg19: chr17-73831953;