rs150861045

Variant names:

• chr17-75834657-G-C
• rs150861045
• NM_199242.3:c.2052C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-75834657-G-C
• chr17-75834657-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_199242.3(UNC13D):​c.2052C>G​(p.Leu684Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,778 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (9 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.685
• Publications: 3 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, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 17-75834657-G-C is Benign according to our data. Variant chr17-75834657-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.685 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00088 (134/152302) while in subpopulation SAS AF = 0.00477 (23/4818). AF 95% confidence interval is 0.00326. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.2052C>G	p.Leu684Leu	synonymous	Exon 22 of 32	NP_954712.1	Q70J99-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.2052C>G	p.Leu684Leu	synonymous	Exon 22 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.2052C>G	p.Leu684Leu	synonymous	Exon 22 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.2052C>G	p.Leu684Leu	synonymous	Exon 23 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00208 AC: 520 AN: 250278 AF XY: 0.00243

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00937

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00123 AC: 1804 AN: 1461476 Hom.: 9 Cov.: 33 AF XY: 0.00148 AC XY: 1078 AN XY: 727020

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00937 AC: 245 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00738 AC: 637 AN: 86258

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53018

Middle Eastern (MID) AF: 0.00884 AC: 51 AN: 5768

European-Non Finnish (NFE) AF: 0.000629 AC: 699 AN: 1112006

Other (OTH) AF: 0.00180 AC: 109 AN: 60390

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000873 AC XY: 65 AN XY: 74468

African (AFR) AF: 0.000192 AC: 8 AN: 41572

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00210 Hom.: 0

Bravo AF: 0.000960

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.9
DANN	Benign	0.81
PhyloP100		0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=99/1	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: rs150861045; hg19: chr17-73830738; COSMIC: COSV104392698;