chr17-75844162-G-A

Variant names:

• chr17-75844162-G-A
• rs3744010
• NM_199242.3:c.117+59C>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.117+59C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,589,986 control chromosomes in the GnomAD database, including 53,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8244 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44788 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.50
• Publications: 8 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=-0.81).
• BP6: Variant 17-75844162-G-A is Benign according to our data. Variant chr17-75844162-G-A is described in ClinVar as Benign. ClinVar VariationId is 1166947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199242.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	NM_199242.3	MANE Select	c.117+59C>T		intron	N/A	NP_954712.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.117+59C>T		intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000588774.2	TSL:3	n.262C>T		non_coding_transcript_exon	Exon 2 of 3
	UNC13D	ENST00000412096.6	TSL:2	c.117+59C>T		intron	N/A	ENSP00000388093.1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46186 AN: 151932 Hom.: 8216 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.303

GnomAD4 exome AF: 0.243 AC: 349789 AN: 1437936 Hom.: 44788 Cov.: 29 AF XY: 0.242 AC XY: 173596 AN XY: 716068

African (AFR) AF: 0.501 AC: 16622 AN: 33184

American (AMR) AF: 0.202 AC: 9033 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 8144 AN: 26048

East Asian (EAS) AF: 0.111 AC: 4399 AN: 39572

South Asian (SAS) AF: 0.216 AC: 18593 AN: 85962

European-Finnish (FIN) AF: 0.178 AC: 7529 AN: 42396

Middle Eastern (MID) AF: 0.346 AC: 1956 AN: 5660

European-Non Finnish (NFE) AF: 0.243 AC: 267854 AN: 1100674

Other (OTH) AF: 0.262 AC: 15659 AN: 59804

GnomAD4 genome AF: 0.304 AC: 46264 AN: 152050 Hom.: 8244 Cov.: 32 AF XY: 0.296 AC XY: 21978 AN XY: 74308

African (AFR) AF: 0.491 AC: 20366 AN: 41450

American (AMR) AF: 0.233 AC: 3559 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1098 AN: 3472

East Asian (EAS) AF: 0.116 AC: 599 AN: 5166

South Asian (SAS) AF: 0.203 AC: 977 AN: 4814

European-Finnish (FIN) AF: 0.175 AC: 1850 AN: 10588

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16831 AN: 67954

Other (OTH) AF: 0.310 AC: 654 AN: 2110

Alfa AF: 0.271 Hom.: 1955

Bravo AF: 0.319

Asia WGS AF: 0.215 AC: 745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported.

Familial hemophagocytic lymphohistiocytosis 3 Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Autoinflammatory syndrome Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.51
DANN	Benign	0.73
PhyloP100		-1.5
PromoterAI		-0.072	Neutral
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: rs3744010; hg19: chr17-73840243; COSMIC: COSV52886233; COSMIC: COSV52886233;