rs35628234

Variant names:

• chr17-75830039-C-T
• rs35628234
• NM_199242.3:c.2943G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_199242.3(UNC13D):​c.2943G>A​(p.Glu981Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0494 in 1,577,316 control chromosomes in the GnomAD database, including 2,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (558 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2009 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.18
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 17-75830039-C-T is Benign according to our data. Variant chr17-75830039-C-T is described in ClinVar as Benign. ClinVar VariationId is 263238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 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.2943G>A	p.Glu981Glu	synonymous	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.2943G>A	p.Glu981Glu	synonymous	Exon 30 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.2943G>A	p.Glu981Glu	synonymous	Exon 30 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.2943G>A	p.Glu981Glu	synonymous	Exon 31 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.0713 AC: 10845 AN: 152156 Hom.: 553 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0835

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0592

GnomAD2 exomes AF: 0.0516 AC: 9828 AN: 190444 AF XY: 0.0536

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0232

Gnomad ASJ exome AF: 0.0588

Gnomad EAS exome AF: 0.0270

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0429

Gnomad OTH exome AF: 0.0516

GnomAD4 exome AF: 0.0471 AC: 67125 AN: 1425042 Hom.: 2009 Cov.: 31 AF XY: 0.0485 AC XY: 34184 AN XY: 705126

African (AFR) AF: 0.148 AC: 4902 AN: 33012

American (AMR) AF: 0.0262 AC: 1005 AN: 38360

Ashkenazi Jewish (ASJ) AF: 0.0575 AC: 1455 AN: 25326

East Asian (EAS) AF: 0.0375 AC: 1441 AN: 38434

South Asian (SAS) AF: 0.0903 AC: 7317 AN: 80986

European-Finnish (FIN) AF: 0.0357 AC: 1814 AN: 50854

Middle Eastern (MID) AF: 0.0717 AC: 410 AN: 5720

European-Non Finnish (NFE) AF: 0.0417 AC: 45643 AN: 1093308

Other (OTH) AF: 0.0531 AC: 3138 AN: 59042

GnomAD4 genome AF: 0.0713 AC: 10862 AN: 152274 Hom.: 558 Cov.: 32 AF XY: 0.0709 AC XY: 5275 AN XY: 74452

African (AFR) AF: 0.141 AC: 5850 AN: 41540

American (AMR) AF: 0.0430 AC: 657 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 220 AN: 3470

East Asian (EAS) AF: 0.0261 AC: 135 AN: 5176

South Asian (SAS) AF: 0.0838 AC: 405 AN: 4832

European-Finnish (FIN) AF: 0.0342 AC: 363 AN: 10622

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0454 AC: 3086 AN: 68024

Other (OTH) AF: 0.0581 AC: 123 AN: 2116

Alfa AF: 0.0597 Hom.: 213

Bravo AF: 0.0730

Asia WGS AF: 0.0570 AC: 200 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.0
DANN	Benign	0.85
PhyloP100		1.2
PromoterAI		-0.026	Neutral
Mutation Taster		=99/1	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: rs35628234; hg19: chr17-73826120; COSMIC: COSV52884810; COSMIC: COSV52884810;