17-75830325-G-C

Variant names:

• chr17-75830325-G-C
• rs2290769
• NM_199242.3:c.2830+37C>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.2830+37C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,584,446 control chromosomes in the GnomAD database, including 37,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3042 hom., cov: 32)
  • Exomes 𝑓: 0.22 (34756 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.466
• Publications: 18 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=-0.8).
• BP6: Variant 17-75830325-G-C is Benign according to our data. Variant chr17-75830325-G-C is described in ClinVar as Benign. ClinVar VariationId is 263236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 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.2830+37C>G		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.2830+37C>G		intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.2830+37C>G		intron	N/A	ENSP00000388093.1
	UNC13D	ENST00000699510.1		c.1696+37C>G		intron	N/A	ENSP00000514405.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29733 AN: 152120 Hom.: 3033 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.177 AC: 36015 AN: 203246 AF XY: 0.180

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.0936

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.217 AC: 310864 AN: 1432208 Hom.: 34756 Cov.: 36 AF XY: 0.216 AC XY: 153409 AN XY: 709550

African (AFR) AF: 0.154 AC: 5089 AN: 33036

American (AMR) AF: 0.135 AC: 5449 AN: 40234

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 5663 AN: 25492

East Asian (EAS) AF: 0.103 AC: 3974 AN: 38714

South Asian (SAS) AF: 0.184 AC: 15095 AN: 82214

European-Finnish (FIN) AF: 0.166 AC: 8410 AN: 50572

Middle Eastern (MID) AF: 0.210 AC: 861 AN: 4104

European-Non Finnish (NFE) AF: 0.231 AC: 253767 AN: 1098614

Other (OTH) AF: 0.212 AC: 12556 AN: 59228

GnomAD4 genome AF: 0.195 AC: 29755 AN: 152238 Hom.: 3042 Cov.: 32 AF XY: 0.191 AC XY: 14191 AN XY: 74428

African (AFR) AF: 0.161 AC: 6681 AN: 41540

American (AMR) AF: 0.166 AC: 2536 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 732 AN: 3472

East Asian (EAS) AF: 0.106 AC: 548 AN: 5170

South Asian (SAS) AF: 0.171 AC: 826 AN: 4828

European-Finnish (FIN) AF: 0.169 AC: 1793 AN: 10606

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15928 AN: 67998

Other (OTH) AF: 0.205 AC: 433 AN: 2116

Alfa AF: 0.212 Hom.: 645

Bravo AF: 0.195

Asia WGS AF: 0.167 AC: 580 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

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 32% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.4
DANN	Benign	0.58
PhyloP100		-0.47
PromoterAI		0.022	Neutral
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: rs2290769; hg19: chr17-73826406; COSMIC: COSV52884143; COSMIC: COSV52884143;