rs560126604

chr17-75842488-G-Achr17-75842488-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199242.3(UNC13D):c.514C>T(p.Arg172Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R172H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.28

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1629656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.514C>T	p.Arg172Cys	missense_variant	6/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.514C>T	p.Arg172Cys	missense_variant	6/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000520 AC: 13 AN: 250196 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461070 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 726826

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000758

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74502

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000982

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 31, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 172 of the UNC13D protein (p.Arg172Cys). This variant is present in population databases (rs560126604, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with UNC13D-related conditions. ClinVar contains an entry for this variant (Variation ID: 533093). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on UNC13D protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.3	M;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N;N;.;.
REVEL	Benign	0.29
Sift	Benign	0.053	T;T;.;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.70
MutPred		0.57		Loss of disorder (P = 0.0192);Loss of disorder (P = 0.0192);.;.;
MVP		0.79
MPC		0.58
ClinPred		0.45	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs560126604; hg19: chr17-73838569; COSMIC: COSV52884065; COSMIC: COSV52884065;