rs118049905

Variant names:

• chr17-75830086-G-A
• rs118049905
• NM_199242.3:c.2896C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-75830086-G-A
• chr17-75830086-G-C

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.2896C>T​(p.Arg966Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,580,010 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R966G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (28 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.63
• Publications: 11 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, Ambry Genetics, ClinGen, 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=0.009559631).
• BP6: Variant 17-75830086-G-A is Benign according to our data. Variant chr17-75830086-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263237.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00373 (568/152280) while in subpopulation NFE AF = 0.00609 (414/68012). AF 95% confidence interval is 0.0056. There are 1 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 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.2896C>T	p.Arg966Trp	missense	Exon 30 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.2896C>T	p.Arg966Trp	missense	Exon 30 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.2896C>T	p.Arg966Trp	missense	Exon 30 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.2896C>T	p.Arg966Trp	missense	Exon 31 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00441 AC: 852 AN: 193394 AF XY: 0.00448

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.00426

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00486

Gnomad NFE exome AF: 0.00763

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00599 AC: 8558 AN: 1427730 Hom.: 28 Cov.: 31 AF XY: 0.00582 AC XY: 4111 AN XY: 706932

African (AFR) AF: 0.000851 AC: 28 AN: 32918

American (AMR) AF: 0.00192 AC: 75 AN: 39044

Ashkenazi Jewish (ASJ) AF: 0.00485 AC: 123 AN: 25386

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38152

South Asian (SAS) AF: 0.000111 AC: 9 AN: 81382

European-Finnish (FIN) AF: 0.00538 AC: 274 AN: 50960

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5720

European-Non Finnish (NFE) AF: 0.00711 AC: 7786 AN: 1095000

Other (OTH) AF: 0.00436 AC: 258 AN: 59168

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74458

African (AFR) AF: 0.00106 AC: 44 AN: 41552

American (AMR) AF: 0.00275 AC: 42 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00442 AC: 47 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00609 AC: 414 AN: 68012

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00547 Hom.: 6

Bravo AF: 0.00326

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00710 AC: 61

ExAC AF: 0.00438 AC: 525

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Familial hemophagocytic lymphohistiocytosis 3 (2)
-	1	1	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	0.040	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.91
MPC		0.51
ClinPred		0.028	T
GERP RS		2.0
PromoterAI		0.0061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.39
gMVP		0.57
Mutation Taster		=87/13	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: rs118049905; hg19: chr17-73826167; COSMIC: COSV52885885; COSMIC: COSV52885885;