rs116229331

Variant names:

• chr17-75840504-C-T
• rs116229331
• NM_199242.3:c.753+3G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_199242.3(UNC13D):​c.753+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,614,062 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0058 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (12 hom.)
• Consequence: UNC13D NM_199242.3 splice_region, intron
• Scores: Splicing: ADA: 0.0009948
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.767
• Publications: 4 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, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 17-75840504-C-T is Benign according to our data. Variant chr17-75840504-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 381715.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00581 (884/152256) while in subpopulation AFR AF = 0.0176 (733/41552). AF 95% confidence interval is 0.0166. There are 6 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.753+3G>A		splice_region intron	N/A	NP_954712.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.753+3G>A		splice_region intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.753+3G>A		splice_region intron	N/A	ENSP00000388093.1
	UNC13D	ENST00000868100.1		c.753+3G>A		splice_region intron	N/A	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 884 AN: 152138 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00252 AC: 634 AN: 251412 AF XY: 0.00221

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00117 AC: 1707 AN: 1461806 Hom.: 12 Cov.: 36 AF XY: 0.00114 AC XY: 831 AN XY: 727200

African (AFR) AF: 0.0173 AC: 578 AN: 33478

American (AMR) AF: 0.00197 AC: 88 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 546 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000284 AC: 316 AN: 1111978

Other (OTH) AF: 0.00285 AC: 172 AN: 60394

GnomAD4 genome AF: 0.00581 AC: 884 AN: 152256 Hom.: 6 Cov.: 32 AF XY: 0.00545 AC XY: 406 AN XY: 74442

African (AFR) AF: 0.0176 AC: 733 AN: 41552

American (AMR) AF: 0.00203 AC: 31 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68002

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00536 Hom.: 12

Bravo AF: 0.00658

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	1	Familial hemophagocytic lymphohistiocytosis 3 (2)
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	UNC13D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	13
DANN	Benign	0.95
PhyloP100		0.77
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00099
dbscSNV1_RF	Benign	0.0080
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: rs116229331; hg19: chr17-73836585;