17-75827307-C-T

Variant names:

• chr17-75827307-C-T
• rs115709152
• NM_199242.3:c.*658G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_199242.3(UNC13D):​c.*658G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 658,788 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0093 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (10 hom.)
• Consequence: UNC13D NM_199242.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.92
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00932 (1419/152224) while in subpopulation AFR AF = 0.0316 (1312/41518). AF 95% confidence interval is 0.0302. There are 13 homozygotes in GnomAd4. There are 671 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.*658G>A		3_prime_UTR_variant	Exon 32 of 32	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.*658G>A		3_prime_UTR_variant	Exon 32 of 32	1	NM_199242.3	ENSP00000207549.3
UNC13D	ENST00000412096.6	c.*163G>A		3_prime_UTR_variant	Exon 33 of 33	2		ENSP00000388093.1
UNC13D	ENST00000589670.5	c.*147G>A		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000466758.1
UNC13D	ENST00000699510.1	c.*658G>A		downstream_gene_variant				ENSP00000514405.1

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1413 AN: 152106 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.000977 AC: 495 AN: 506564 Hom.: 10 Cov.: 8 AF XY: 0.000788 AC XY: 199 AN XY: 252496

African (AFR) AF: 0.0293 AC: 370 AN: 12632

American (AMR) AF: 0.00327 AC: 40 AN: 12224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11744

East Asian (EAS) AF: 0.00 AC: 0 AN: 26284

South Asian (SAS) AF: 0.000157 AC: 3 AN: 19050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24080

Middle Eastern (MID) AF: 0.000527 AC: 1 AN: 1898

European-Non Finnish (NFE) AF: 0.0000832 AC: 31 AN: 372784

Other (OTH) AF: 0.00193 AC: 50 AN: 25868

GnomAD4 genome AF: 0.00932 AC: 1419 AN: 152224 Hom.: 13 Cov.: 32 AF XY: 0.00902 AC XY: 671 AN XY: 74430

African (AFR) AF: 0.0316 AC: 1312 AN: 41518

American (AMR) AF: 0.00477 AC: 73 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67998

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00803 Hom.: 2

Bravo AF: 0.0111

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.042
DANN	Benign	0.52
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs115709152; hg19: chr17-73823388;