rs1135688

Variant names:

• chr17-75831124-T-C
• rs1135688
• NM_199242.3:c.2599A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-75831124-T-C
• chr17-75831124-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199242.3(UNC13D):​c.2599A>G​(p.Lys867Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,613,702 control chromosomes in the GnomAD database, including 107,159 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (20270 hom., cov: 33)
  • Exomes 𝑓: 0.33 (86889 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 1.07
• Publications: 48 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

ENSG00000302174 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.4924445E-7).
• BP6: Variant 17-75831124-T-C is Benign according to our data. Variant chr17-75831124-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

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.2599A>G	p.Lys867Glu	missense	Exon 27 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.2599A>G	p.Lys867Glu	missense	Exon 27 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.2599A>G	p.Lys867Glu	missense	Exon 27 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.2599A>G	p.Lys867Glu	missense	Exon 28 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70060 AN: 152032 Hom.: 20220 Cov.: 33

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.451

GnomAD2 exomes AF: 0.353 AC: 88391 AN: 250424 AF XY: 0.350

Gnomad AFR exome AF: 0.844

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.427

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.320

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.332 AC: 485186 AN: 1461550 Hom.: 86889 Cov.: 54 AF XY: 0.332 AC XY: 241665 AN XY: 727052

African (AFR) AF: 0.846 AC: 28314 AN: 33480

American (AMR) AF: 0.255 AC: 11401 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 11064 AN: 26136

East Asian (EAS) AF: 0.439 AC: 17441 AN: 39696

South Asian (SAS) AF: 0.357 AC: 30772 AN: 86252

European-Finnish (FIN) AF: 0.232 AC: 12326 AN: 53172

Middle Eastern (MID) AF: 0.495 AC: 2858 AN: 5768

European-Non Finnish (NFE) AF: 0.314 AC: 348807 AN: 1111954

Other (OTH) AF: 0.368 AC: 22203 AN: 60382

GnomAD4 genome AF: 0.461 AC: 70162 AN: 152152 Hom.: 20270 Cov.: 33 AF XY: 0.452 AC XY: 33627 AN XY: 74374

African (AFR) AF: 0.826 AC: 34313 AN: 41542

American (AMR) AF: 0.319 AC: 4877 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1496 AN: 3470

East Asian (EAS) AF: 0.427 AC: 2210 AN: 5170

South Asian (SAS) AF: 0.343 AC: 1651 AN: 4820

European-Finnish (FIN) AF: 0.228 AC: 2417 AN: 10588

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21869 AN: 67966

Other (OTH) AF: 0.455 AC: 958 AN: 2106

Alfa AF: 0.391 Hom.: 23880

Bravo AF: 0.488

TwinsUK AF: 0.312 AC: 1157

ALSPAC AF: 0.317 AC: 1222

ESP6500AA AF: 0.820 AC: 3612

ESP6500EA AF: 0.326 AC: 2800

ExAC AF: 0.365 AC: 44265

Asia WGS AF: 0.418 AC: 1453 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Familial hemophagocytic lymphohistiocytosis 3 (4)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.7
DANN	Benign	0.16
DEOGEN2	Benign	0.047	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.096	T
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.5	N
PhyloP100		1.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.14
ClinPred		0.00042	T
GERP RS		3.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.096
gMVP		0.084
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1135688; hg19: chr17-73827205; COSMIC: COSV52884077; COSMIC: COSV52884077;