NM_199242.3:c.1389+36G>A

Variant names:

• chr17-75836303-C-T
• rs74410877
• NM_199242.3:c.1389+36G>A

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.1389+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,612,904 control chromosomes in the GnomAD database, including 10,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (750 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9672 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.789
• Publications: 9 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=-0.91).
• BP6: Variant 17-75836303-C-T is Benign according to our data. Variant chr17-75836303-C-T is described in ClinVar as Benign. ClinVar VariationId is 263212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.1389+36G>A		intron_variant	Intron 15 of 31	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.1389+36G>A		intron_variant	Intron 15 of 31	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes AF: 0.0854 AC: 12995 AN: 152178 Hom.: 747 Cov.: 33

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0963

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0888

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.0925 AC: 22906 AN: 247590 AF XY: 0.0927

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.0848

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0850

Gnomad FIN exome AF: 0.0815

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.111 AC: 162552 AN: 1460608 Hom.: 9672 Cov.: 40 AF XY: 0.110 AC XY: 79774 AN XY: 726488

African (AFR) AF: 0.0183 AC: 611 AN: 33474

American (AMR) AF: 0.0859 AC: 3829 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 3441 AN: 26084

East Asian (EAS) AF: 0.0916 AC: 3636 AN: 39674

South Asian (SAS) AF: 0.0431 AC: 3712 AN: 86098

European-Finnish (FIN) AF: 0.0848 AC: 4495 AN: 53018

Middle Eastern (MID) AF: 0.0989 AC: 570 AN: 5762

European-Non Finnish (NFE) AF: 0.122 AC: 135550 AN: 1111576

Other (OTH) AF: 0.111 AC: 6708 AN: 60354

GnomAD4 genome AF: 0.0854 AC: 13002 AN: 152296 Hom.: 750 Cov.: 33 AF XY: 0.0832 AC XY: 6197 AN XY: 74462

African (AFR) AF: 0.0219 AC: 912 AN: 41586

American (AMR) AF: 0.0961 AC: 1470 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3472

East Asian (EAS) AF: 0.0894 AC: 463 AN: 5180

South Asian (SAS) AF: 0.0394 AC: 190 AN: 4828

European-Finnish (FIN) AF: 0.0760 AC: 807 AN: 10614

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8378 AN: 68000

Other (OTH) AF: 0.110 AC: 232 AN: 2114

Alfa AF: 0.105 Hom.: 192

Bravo AF: 0.0861

Asia WGS AF: 0.0780 AC: 269 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

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 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -

Familial hemophagocytic lymphohistiocytosis 3 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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_noAF	Benign	-0.91
CADD	Benign	0.98
DANN	Benign	0.39
PhyloP100		-0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs74410877; hg19: chr17-73832384; COSMIC: COSV104392524;