rs113861754

Variant names:

• chr17-75834107-C-T
• rs113861754
• NM_199242.3:c.2335G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-75834107-C-T
• chr17-75834107-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_199242.3(UNC13D):​c.2335G>A​(p.Val779Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,613,834 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V779V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (22 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 0.738
• Publications: 14 publications found

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]

UNC13D Gene-Disease associations (from GenCC):

• familial hemophagocytic lymphohistiocytosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039931834).
• BP6: Variant 17-75834107-C-T is Benign according to our data. Variant chr17-75834107-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 403593.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00349 (531/152354) while in subpopulation NFE AF = 0.00569 (387/68028). AF 95% confidence interval is 0.00522. There are 0 homozygotes in GnomAd4. There are 256 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199242.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	NM_199242.3	MANE Select	c.2335G>A	p.Val779Met	missense	Exon 24 of 32	NP_954712.1	Q70J99-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.2335G>A	p.Val779Met	missense	Exon 24 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.2335G>A	p.Val779Met	missense	Exon 24 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.2335G>A	p.Val779Met	missense	Exon 25 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 531 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00569

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00297 AC: 744 AN: 250866 AF XY: 0.00321

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.00455

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00423 AC: 6179 AN: 1461480 Hom.: 22 Cov.: 33 AF XY: 0.00411 AC XY: 2986 AN XY: 727040

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00188 AC: 84 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00146 AC: 126 AN: 86258

European-Finnish (FIN) AF: 0.00332 AC: 176 AN: 53034

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00490 AC: 5446 AN: 1111996

Other (OTH) AF: 0.00421 AC: 254 AN: 60386

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.00344 AC XY: 256 AN XY: 74502

African (AFR) AF: 0.000793 AC: 33 AN: 41588

American (AMR) AF: 0.00340 AC: 52 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00329 AC: 35 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00569 AC: 387 AN: 68028

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00413 Hom.: 2

Bravo AF: 0.00310

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00292 AC: 354

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00462

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Familial hemophagocytic lymphohistiocytosis 3 (2)
-	1	1	not specified (2)
-	1	-	Autoinflammatory syndrome (1)
-	-	1	Intellectual disability (1)
-	-	1	UNC13D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.74
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.021
Sift	Benign	0.076	T
Sift4G	Benign	0.087	T
Polyphen		0.031	B
Vest4		0.14
MVP		0.65
MPC		0.10
ClinPred		0.0047	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.19
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs113861754; hg19: chr17-73830188; COSMIC: COSV99257762; COSMIC: COSV99257762;