rs145607492

Positions:

• chr17-75840775-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_199242.3(UNC13D):​c.670C>T​(p.His224Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00016 in 1,613,882 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.56

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14394236).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.670C>T	p.His224Tyr	missense_variant	8/32	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.670C>T	p.His224Tyr	missense_variant	8/32	1	NM_199242.3	ENSP00000207549	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251328 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461712 Hom.: 2 Cov.: 35 AF XY: 0.000165 AC XY: 120 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 224 of the UNC13D protein (p.His224Tyr). This variant is present in population databases (rs145607492, gnomAD 0.1%). This missense change has been observed in individual(s) with primary immunodeficiency (PMID: 32135276). ClinVar contains an entry for this variant (Variation ID: 464459). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2022	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

UNC13D: PM2, PM3:Supporting, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.4	N;N;.;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.022	D;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.67
MVP		0.84
MPC		0.52
ClinPred		0.22	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.31

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: rs145607492; hg19: chr17-73836856;