rs35037984

Variant names:

• chr17-75830410-G-A
• rs35037984
• NM_199242.3:c.2782C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-75830410-G-A
• chr17-75830410-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_199242.3(UNC13D):​c.2782C>T​(p.Arg928Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,588,302 control chromosomes in the GnomAD database, including 390 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. R928H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (36 hom., cov: 33)
  • Exomes 𝑓: 0.021 (354 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.92
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008826911).
• BP6: Variant 17-75830410-G-A is Benign according to our data. Variant chr17-75830410-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0173 (2628/152264) while in subpopulation AMR AF = 0.0256 (392/15296). AF 95% confidence interval is 0.0235. There are 36 homozygotes in GnomAd4. There are 1266 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 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.2782C>T	p.Arg928Cys	missense	Exon 29 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.2782C>T	p.Arg928Cys	missense	Exon 29 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.2782C>T	p.Arg928Cys	missense	Exon 29 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.2782C>T	p.Arg928Cys	missense	Exon 30 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2629 AN: 152146 Hom.: 36 Cov.: 33

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0196

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0190 AC: 3894 AN: 205488 AF XY: 0.0198

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.0000639

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0214

GnomAD4 exome AF: 0.0205 AC: 29491 AN: 1436038 Hom.: 354 Cov.: 34 AF XY: 0.0208 AC XY: 14828 AN XY: 712082

African (AFR) AF: 0.00332 AC: 110 AN: 33088

American (AMR) AF: 0.0127 AC: 515 AN: 40608

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 409 AN: 25572

East Asian (EAS) AF: 0.0000774 AC: 3 AN: 38754

South Asian (SAS) AF: 0.0224 AC: 1842 AN: 82402

European-Finnish (FIN) AF: 0.0209 AC: 1065 AN: 51030

Middle Eastern (MID) AF: 0.0354 AC: 153 AN: 4318

European-Non Finnish (NFE) AF: 0.0221 AC: 24285 AN: 1100930

Other (OTH) AF: 0.0187 AC: 1109 AN: 59336

GnomAD4 genome AF: 0.0173 AC: 2628 AN: 152264 Hom.: 36 Cov.: 33 AF XY: 0.0170 AC XY: 1266 AN XY: 74440

African (AFR) AF: 0.00332 AC: 138 AN: 41560

American (AMR) AF: 0.0256 AC: 392 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 64 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4832

European-Finnish (FIN) AF: 0.0185 AC: 196 AN: 10592

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0244 AC: 1657 AN: 68018

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0239 Hom.: 109

Bravo AF: 0.0157

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00296 AC: 13

ESP6500EA AF: 0.0225 AC: 193

ExAC AF: 0.0165 AC: 1984

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Familial hemophagocytic lymphohistiocytosis 3 (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.6	N
REVEL	Uncertain	0.40
Sift	Benign	0.13	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.41	B
Vest4		0.20
MPC		0.17
ClinPred		0.0075	T
GERP RS		2.9
PromoterAI		0.0018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.11
gMVP		0.45
Mutation Taster		=82/18	polymorphism (auto)

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: rs35037984; hg19: chr17-73826491; COSMIC: COSV104392540;