rs113904350

Variant names:

• chr17-75827901-G-A
• rs113904350
• NM_199242.3:c.*64C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.822
• Publications: 1 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 -20 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. 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.*64C>T		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.*64C>T		3_prime_UTR_variant	Exon 32 of 32	1	NM_199242.3	ENSP00000207549.3

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

African (AFR) AF: 0.0140 AC: 452 AN: 32230

American (AMR) AF: 0.00641 AC: 259 AN: 40430

Ashkenazi Jewish (ASJ) AF: 0.0358 AC: 908 AN: 25360

East Asian (EAS) AF: 0.000324 AC: 12 AN: 37012

South Asian (SAS) AF: 0.0142 AC: 1162 AN: 82058

European-Finnish (FIN) AF: 0.000737 AC: 32 AN: 43432

Middle Eastern (MID) AF: 0.0273 AC: 112 AN: 4104

European-Non Finnish (NFE) AF: 0.00439 AC: 4802 AN: 1094410

Other (OTH) AF: 0.00853 AC: 500 AN: 58646

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

African (AFR) AF: 0.0136 AC: 566 AN: 41576

American (AMR) AF: 0.00634 AC: 97 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4830

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00471 AC: 320 AN: 68004

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.7
DANN	Benign	0.82
PhyloP100		0.82
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: rs113904350; hg19: chr17-73823982;