rs112341334

Variant names:

• chr17-75834310-G-A
• rs112341334
• NM_199242.3:c.2298+15C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-75834310-G-A
• chr17-75834310-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_199242.3(UNC13D):​c.2298+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,592,864 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (53 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.367
• Publications: 1 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 17-75834310-G-A is Benign according to our data. Variant chr17-75834310-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00802 (1221/152330) while in subpopulation AFR AF = 0.0146 (609/41576). AF 95% confidence interval is 0.0137. There are 11 homozygotes in GnomAd4. There are 551 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.2298+15C>T		intron_variant	Intron 23 of 31	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.2298+15C>T		intron_variant	Intron 23 of 31	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes AF: 0.00799 AC: 1216 AN: 152212 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00493

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00741 AC: 1657 AN: 223690 AF XY: 0.00755

Gnomad AFR exome AF: 0.0152

Gnomad AMR exome AF: 0.00611

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.00528

Gnomad OTH exome AF: 0.00808

GnomAD4 exome AF: 0.00567 AC: 8175 AN: 1440534 Hom.: 53 Cov.: 33 AF XY: 0.00591 AC XY: 4234 AN XY: 716660

African (AFR) AF: 0.0150 AC: 500 AN: 33322

American (AMR) AF: 0.00631 AC: 278 AN: 44056

Ashkenazi Jewish (ASJ) AF: 0.0252 AC: 656 AN: 25984

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39406

South Asian (SAS) AF: 0.0123 AC: 1052 AN: 85352

European-Finnish (FIN) AF: 0.000941 AC: 36 AN: 38258

Middle Eastern (MID) AF: 0.0143 AC: 63 AN: 4402

European-Non Finnish (NFE) AF: 0.00463 AC: 5143 AN: 1109798

Other (OTH) AF: 0.00742 AC: 445 AN: 59956

GnomAD4 genome AF: 0.00802 AC: 1221 AN: 152330 Hom.: 11 Cov.: 33 AF XY: 0.00740 AC XY: 551 AN XY: 74502

African (AFR) AF: 0.0146 AC: 609 AN: 41576

American (AMR) AF: 0.00693 AC: 106 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4834

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00493 AC: 335 AN: 68010

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.00679 Hom.: 2

Bravo AF: 0.00885

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	-0.80
CADD	Benign	0.24
DANN	Benign	0.79
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism

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: rs112341334; hg19: chr17-73830391; COSMIC: COSV104392644;