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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	NM_199242.3	MANE Select	c.2298+15C>T		intron	N/A	NP_954712.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.2298+15C>T		intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.2298+15C>T		intron	N/A	ENSP00000388093.1
	UNC13D	ENST00000868100.1		c.2298+15C>T		intron	N/A	ENSP00000538159.1

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial hemophagocytic lymphohistiocytosis 3 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;