chr17-75841061-A-C

Variant names:

• chr17-75841061-A-C
• rs8067076
• NM_199242.3:c.570-60T>G

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.570-60T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,603,944 control chromosomes in the GnomAD database, including 109,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (20296 hom., cov: 28)
  • Exomes 𝑓: 0.34 (89615 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.408
• Publications: 23 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=-1.0).
• BP6: Variant 17-75841061-A-C is Benign according to our data. Variant chr17-75841061-A-C is described in ClinVar as Benign. ClinVar VariationId is 1249408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.570-60T>G		intron_variant	Intron 6 of 31	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.570-60T>G		intron_variant	Intron 6 of 31	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70062 AN: 150622 Hom.: 20246 Cov.: 28

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.455

GnomAD4 exome AF: 0.340 AC: 493881 AN: 1453214 Hom.: 89615 Cov.: 30 AF XY: 0.340 AC XY: 245972 AN XY: 723416

African (AFR) AF: 0.847 AC: 28273 AN: 33374

American (AMR) AF: 0.261 AC: 11647 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 10707 AN: 26030

East Asian (EAS) AF: 0.430 AC: 17015 AN: 39564

South Asian (SAS) AF: 0.363 AC: 31226 AN: 86022

European-Finnish (FIN) AF: 0.240 AC: 12711 AN: 52964

Middle Eastern (MID) AF: 0.497 AC: 2847 AN: 5730

European-Non Finnish (NFE) AF: 0.323 AC: 357083 AN: 1104816

Other (OTH) AF: 0.372 AC: 22372 AN: 60062

GnomAD4 genome AF: 0.465 AC: 70162 AN: 150730 Hom.: 20296 Cov.: 28 AF XY: 0.457 AC XY: 33591 AN XY: 73510

African (AFR) AF: 0.827 AC: 33951 AN: 41048

American (AMR) AF: 0.323 AC: 4873 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1462 AN: 3466

East Asian (EAS) AF: 0.417 AC: 2134 AN: 5118

South Asian (SAS) AF: 0.351 AC: 1675 AN: 4768

European-Finnish (FIN) AF: 0.238 AC: 2421 AN: 10152

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22302 AN: 67786

Other (OTH) AF: 0.460 AC: 959 AN: 2086

Alfa AF: 0.358 Hom.: 12858

Bravo AF: 0.492

Asia WGS AF: 0.409 AC: 1422 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 33. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.1
DANN	Benign	0.44
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs8067076; hg19: chr17-73837142; COSMIC: COSV52883035; COSMIC: COSV52883035;