17-75843133-G-C

Variant names:

• chr17-75843133-G-C
• rs3744008
• NM_199242.3:c.261+26C>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.261+26C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,610,152 control chromosomes in the GnomAD database, including 40,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3612 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36417 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.680
• Publications: 10 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=-0.83).
• BP6: Variant 17-75843133-G-C is Benign according to our data. Variant chr17-75843133-G-C is described in ClinVar as Benign. ClinVar VariationId is 263229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.261+26C>G		intron_variant	Intron 3 of 31	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.261+26C>G		intron_variant	Intron 3 of 31	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32602 AN: 151922 Hom.: 3602 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0892

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.218

GnomAD2 exomes AF: 0.197 AC: 48293 AN: 245626 AF XY: 0.199

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.226

Gnomad EAS exome AF: 0.0845

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.221 AC: 321663 AN: 1458112 Hom.: 36417 Cov.: 37 AF XY: 0.220 AC XY: 159521 AN XY: 725432

African (AFR) AF: 0.227 AC: 7597 AN: 33444

American (AMR) AF: 0.145 AC: 6490 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 6016 AN: 26128

East Asian (EAS) AF: 0.0910 AC: 3610 AN: 39692

South Asian (SAS) AF: 0.187 AC: 16083 AN: 86212

European-Finnish (FIN) AF: 0.175 AC: 8829 AN: 50508

Middle Eastern (MID) AF: 0.226 AC: 1217 AN: 5382

European-Non Finnish (NFE) AF: 0.233 AC: 258648 AN: 1111730

Other (OTH) AF: 0.218 AC: 13173 AN: 60306

GnomAD4 genome AF: 0.215 AC: 32630 AN: 152040 Hom.: 3612 Cov.: 32 AF XY: 0.209 AC XY: 15561 AN XY: 74334

African (AFR) AF: 0.225 AC: 9330 AN: 41462

American (AMR) AF: 0.175 AC: 2680 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3466

East Asian (EAS) AF: 0.0897 AC: 464 AN: 5170

South Asian (SAS) AF: 0.169 AC: 815 AN: 4820

European-Finnish (FIN) AF: 0.173 AC: 1834 AN: 10588

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15992 AN: 67938

Other (OTH) AF: 0.225 AC: 476 AN: 2114

Alfa AF: 0.152 Hom.: 398

Bravo AF: 0.217

Asia WGS AF: 0.169 AC: 585 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

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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	-0.83
CADD	Benign	4.5
DANN	Benign	0.71
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3744008; hg19: chr17-73839214; COSMIC: COSV52888505; COSMIC: COSV52888505;