17-75827901-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_199242.3(UNC13D):c.*64C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,570,002 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (77 hom.)
• Consequence: UNC13D NM_199242.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.822

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-75827901-G-A is Benign according to our data. Variant chr17-75827901-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 325239.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0079 (1204/152320) while in subpopulation AFR AF= 0.0136 (566/41576). AF 95% confidence interval is 0.0127. There are 13 homozygotes in gnomad4. There are 531 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.*64C>T		3_prime_UTR_variant	32/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.*64C>T		3_prime_UTR_variant	32/32	1	NM_199242.3	P1
UNC13D	ENST00000699510.1	c.*64C>T		3_prime_UTR_variant	20/20
UNC13D	ENST00000412096.6	c.3240+97C>T		intron_variant		2
UNC13D	ENST00000589670.5	c.*8+56C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1198 AN: 152202 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00634

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00471

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.00581 AC: 8239 AN: 1417682 Hom.: 77 Cov.: 31 AF XY: 0.00612 AC XY: 4299 AN XY: 702930

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.00641

Gnomad4 ASJ exome AF: 0.0358

Gnomad4 EAS exome AF: 0.000324

Gnomad4 SAS exome AF: 0.0142

Gnomad4 FIN exome AF: 0.000737

Gnomad4 NFE exome AF: 0.00439

Gnomad4 OTH exome AF: 0.00853

GnomAD4 genome AF: 0.00790 AC: 1204 AN: 152320 Hom.: 13 Cov.: 33 AF XY: 0.00713 AC XY: 531 AN XY: 74484

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00471

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00664 Hom.: 1

Bravo AF: 0.00851

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.7
Dann	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs113904350; hg19: chr17-73823982;