rs75853379

Variant names:

• chr17-75835513-G-A
• rs75853379
• NM_199242.3:c.1744C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000207549.9(UNC13D):​c.1744C>T​(p.Leu582Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,606,538 control chromosomes in the GnomAD database, including 299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (134 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (165 hom.)
• Consequence: UNC13D ENST00000207549.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.41
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 17-75835513-G-A is Benign according to our data. Variant chr17-75835513-G-A is described in ClinVar as Benign. ClinVar VariationId is 263218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000207549.9. 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.1744C>T	p.Leu582Leu	synonymous	Exon 20 of 32	NP_954712.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.1744C>T	p.Leu582Leu	synonymous	Exon 20 of 32	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.1744C>T	p.Leu582Leu	synonymous	Exon 20 of 33	ENSP00000388093.1
	UNC13D	ENST00000699510.1		c.679C>T	p.Leu227Leu	synonymous	Exon 8 of 20	ENSP00000514405.1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3773 AN: 152184 Hom.: 133 Cov.: 33

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0208

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0144 AC: 3339 AN: 232320 AF XY: 0.0122

Gnomad AFR exome AF: 0.0815

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.00207

Gnomad EAS exome AF: 0.0270

Gnomad FIN exome AF: 0.000674

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00942

GnomAD4 exome AF: 0.00491 AC: 7147 AN: 1454236 Hom.: 165 Cov.: 33 AF XY: 0.00482 AC XY: 3487 AN XY: 722852

African (AFR) AF: 0.0759 AC: 2530 AN: 33328

American (AMR) AF: 0.0321 AC: 1396 AN: 43488

Ashkenazi Jewish (ASJ) AF: 0.00258 AC: 67 AN: 25954

East Asian (EAS) AF: 0.0175 AC: 685 AN: 39226

South Asian (SAS) AF: 0.0126 AC: 1073 AN: 85494

European-Finnish (FIN) AF: 0.000919 AC: 48 AN: 52238

Middle Eastern (MID) AF: 0.00925 AC: 53 AN: 5732

European-Non Finnish (NFE) AF: 0.000593 AC: 658 AN: 1108736

Other (OTH) AF: 0.0106 AC: 637 AN: 60040

GnomAD4 genome AF: 0.0249 AC: 3789 AN: 152302 Hom.: 134 Cov.: 33 AF XY: 0.0245 AC XY: 1823 AN XY: 74486

African (AFR) AF: 0.0759 AC: 3154 AN: 41562

American (AMR) AF: 0.0206 AC: 315 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.0253 AC: 131 AN: 5172

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4828

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68026

Other (OTH) AF: 0.0217 AC: 46 AN: 2116

Alfa AF: 0.0123 Hom.: 38

Bravo AF: 0.0295

Asia WGS AF: 0.0240 AC: 82 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.6
DANN	Benign	0.91
PhyloP100		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs75853379; hg19: chr17-73831594; COSMIC: COSV104392665;