17-75831355-CG-CGG

Variant names:

• chr17-75831355-C-CG
• rs3217698
• NM_199242.3:c.2448-8dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_199242.3(UNC13D):​c.2448-8dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,609,058 control chromosomes in the GnomAD database, including 22,339 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (8033 hom., cov: 28)
  • Exomes 𝑓: 0.099 (14306 hom.)
• Consequence: UNC13D NM_199242.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.316
• Publications: 3 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

ENSG00000302174 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-75831355-C-CG is Benign according to our data. Variant chr17-75831355-C-CG is described in ClinVar as Benign. ClinVar VariationId is 263226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 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.2448-8dupC		splice_region intron	N/A	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.2448-8dupC		splice_region intron	N/A	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.2448-8dupC		splice_region intron	N/A	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.2448-8dupC		splice_region intron	N/A	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35625 AN: 151958 Hom.: 8007 Cov.: 28

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0549

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.0731

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.147 AC: 35586 AN: 242408 AF XY: 0.141

Gnomad AFR exome AF: 0.605

Gnomad AMR exome AF: 0.0971

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.333

Gnomad FIN exome AF: 0.0530

Gnomad NFE exome AF: 0.0747

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.0992 AC: 144541 AN: 1456982 Hom.: 14306 Cov.: 32 AF XY: 0.101 AC XY: 72890 AN XY: 724952

African (AFR) AF: 0.608 AC: 20343 AN: 33440

American (AMR) AF: 0.102 AC: 4556 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 4738 AN: 26100

East Asian (EAS) AF: 0.340 AC: 13478 AN: 39676

South Asian (SAS) AF: 0.167 AC: 14388 AN: 86198

European-Finnish (FIN) AF: 0.0555 AC: 2742 AN: 49396

Middle Eastern (MID) AF: 0.261 AC: 1500 AN: 5758

European-Non Finnish (NFE) AF: 0.0671 AC: 74539 AN: 1111438

Other (OTH) AF: 0.137 AC: 8257 AN: 60314

GnomAD4 genome AF: 0.235 AC: 35692 AN: 152076 Hom.: 8033 Cov.: 28 AF XY: 0.232 AC XY: 17240 AN XY: 74330

African (AFR) AF: 0.587 AC: 24345 AN: 41454

American (AMR) AF: 0.135 AC: 2060 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 701 AN: 3470

East Asian (EAS) AF: 0.326 AC: 1679 AN: 5152

South Asian (SAS) AF: 0.169 AC: 816 AN: 4816

European-Finnish (FIN) AF: 0.0549 AC: 582 AN: 10606

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.0731 AC: 4971 AN: 67978

Other (OTH) AF: 0.214 AC: 453 AN: 2116

Alfa AF: 0.161 Hom.: 742

Bravo AF: 0.258

EpiCase AF: 0.0856

EpiControl AF: 0.0853

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3217698; hg19: chr17-73827436;