NM_199242.3:c.1728-48T>C

Variant names:

• chr17-75835577-A-G
• rs3744024
• NM_199242.3:c.1728-48T>C

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.1728-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,608,438 control chromosomes in the GnomAD database, including 20,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (7615 hom., cov: 33)
  • Exomes 𝑓: 0.093 (13037 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.114
• Publications: 6 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=-0.93).
• BP6: Variant 17-75835577-A-G is Benign according to our data. Variant chr17-75835577-A-G is described in ClinVar as Benign. ClinVar VariationId is 263217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.568 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.1728-48T>C		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.1728-48T>C		intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.1728-48T>C		intron	N/A	ENSP00000388093.1
	UNC13D	ENST00000699510.1		c.663-48T>C		intron	N/A	ENSP00000514405.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34519 AN: 152028 Hom.: 7596 Cov.: 33

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.0683

Gnomad OTH AF: 0.205

GnomAD2 exomes AF: 0.139 AC: 33088 AN: 238450 AF XY: 0.132

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.0925

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.337

Gnomad FIN exome AF: 0.0508

Gnomad NFE exome AF: 0.0693

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.0932 AC: 135673 AN: 1456292 Hom.: 13037 Cov.: 35 AF XY: 0.0941 AC XY: 68176 AN XY: 724146

African (AFR) AF: 0.594 AC: 19790 AN: 33312

American (AMR) AF: 0.0974 AC: 4287 AN: 44036

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4038 AN: 26042

East Asian (EAS) AF: 0.337 AC: 13261 AN: 39308

South Asian (SAS) AF: 0.151 AC: 12896 AN: 85644

European-Finnish (FIN) AF: 0.0533 AC: 2780 AN: 52142

Middle Eastern (MID) AF: 0.248 AC: 1413 AN: 5704

European-Non Finnish (NFE) AF: 0.0625 AC: 69390 AN: 1109962

Other (OTH) AF: 0.130 AC: 7818 AN: 60142

GnomAD4 genome AF: 0.227 AC: 34580 AN: 152146 Hom.: 7615 Cov.: 33 AF XY: 0.225 AC XY: 16739 AN XY: 74394

African (AFR) AF: 0.574 AC: 23823 AN: 41504

American (AMR) AF: 0.130 AC: 1984 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 618 AN: 3470

East Asian (EAS) AF: 0.329 AC: 1698 AN: 5166

South Asian (SAS) AF: 0.154 AC: 744 AN: 4822

European-Finnish (FIN) AF: 0.0529 AC: 561 AN: 10610

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.0683 AC: 4642 AN: 67970

Other (OTH) AF: 0.202 AC: 428 AN: 2114

Alfa AF: 0.152 Hom.: 711

Bravo AF: 0.250

Asia WGS AF: 0.231 AC: 804 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.

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.7
DANN	Benign	0.47
PhyloP100		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=4/96	disease causing

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: rs3744024; hg19: chr17-73831658; COSMIC: COSV52887762; COSMIC: COSV52887762;