17-75827639-G-A

Variant names:

• chr17-75827639-G-A
• rs9916685
• NM_199242.3:c.*326C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199242.3(UNC13D):​c.*326C>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 0.0502 in 1,535,128 control chromosomes in the GnomAD database, including 3,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (873 hom., cov: 33)
  • Exomes 𝑓: 0.047 (2141 hom.)
• Consequence: UNC13D NM_199242.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0640
• Publications: 7 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 (MetaRNN=0.0011135638).
• BP6: Variant 17-75827639-G-A is Benign according to our data. Variant chr17-75827639-G-A is described in ClinVar as [Benign]. Clinvar id is 325237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.*326C>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.*326C>T		3_prime_UTR_variant	Exon 32 of 32	1	NM_199242.3	ENSP00000207549.3
UNC13D	ENST00000412096.6	c.3260C>T	p.Ser1087Phe	missense_variant	Exon 33 of 33	2		ENSP00000388093.1
UNC13D	ENST00000699510.1	c.*326C>T		3_prime_UTR_variant	Exon 20 of 20			ENSP00000514405.1
UNC13D	ENST00000589670.5	c.*9-194C>T		intron_variant	Intron 3 of 3	3		ENSP00000466758.1

Frequencies

GnomAD3 genomes AF: 0.0832 AC: 12657 AN: 152176 Hom.: 868 Cov.: 33

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0616

Gnomad FIN AF: 0.0341

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0455

Gnomad OTH AF: 0.0664

GnomAD2 exomes AF: 0.0485 AC: 6332 AN: 130544 AF XY: 0.0503

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.0569

Gnomad EAS exome AF: 0.000288

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0429

Gnomad OTH exome AF: 0.0527

GnomAD4 exome AF: 0.0466 AC: 64420 AN: 1382834 Hom.: 2141 Cov.: 31 AF XY: 0.0473 AC XY: 32255 AN XY: 682258

African (AFR) AF: 0.205 AC: 6463 AN: 31586

American (AMR) AF: 0.0300 AC: 1069 AN: 35674

Ashkenazi Jewish (ASJ) AF: 0.0560 AC: 1409 AN: 25164

East Asian (EAS) AF: 0.000168 AC: 6 AN: 35724

South Asian (SAS) AF: 0.0677 AC: 5361 AN: 79194

European-Finnish (FIN) AF: 0.0365 AC: 1222 AN: 33462

Middle Eastern (MID) AF: 0.0797 AC: 450 AN: 5646

European-Non Finnish (NFE) AF: 0.0420 AC: 45315 AN: 1078518

Other (OTH) AF: 0.0540 AC: 3125 AN: 57866

GnomAD4 genome AF: 0.0833 AC: 12684 AN: 152294 Hom.: 873 Cov.: 33 AF XY: 0.0817 AC XY: 6082 AN XY: 74474

African (AFR) AF: 0.188 AC: 7822 AN: 41528

American (AMR) AF: 0.0471 AC: 721 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0621 AC: 300 AN: 4832

European-Finnish (FIN) AF: 0.0341 AC: 362 AN: 10626

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0455 AC: 3096 AN: 68032

Other (OTH) AF: 0.0652 AC: 138 AN: 2116

Alfa AF: 0.0562 Hom.: 279

Bravo AF: 0.0874

TwinsUK AF: 0.0402 AC: 149

ALSPAC AF: 0.0441 AC: 170

ExAC AF: 0.0430 AC: 819

Asia WGS AF: 0.0350 AC: 121 AN: 3478

ClinVar

Significance: 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: 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.0
DANN	Benign	0.60
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.064
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.049
Sift	Pathogenic	0.0	D
Vest4		0.056
ClinPred		0.0065	T
GERP RS		1.6
Mutation Taster		=98/2	polymorphism (auto)

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: rs9916685; hg19: chr17-73823720;