chr17-75840065-G-A

Variant names:

• chr17-75840065-G-A
• rs55661958
• NM_199242.3:c.904C>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.904C>T​(p.Leu302Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,592 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L302L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (29 hom.)
• Consequence: UNC13D NM_199242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.05
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002488196).
• BP6: Variant 17-75840065-G-A is Benign according to our data. Variant chr17-75840065-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 325269.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 = 0.0098 (1492/152310) while in subpopulation AFR AF = 0.0339 (1408/41564). AF 95% confidence interval is 0.0324. There are 24 homozygotes in GnomAd4. There are 720 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.904C>T	p.Leu302Phe	missense	Exon 11 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.904C>T	p.Leu302Phe	missense	Exon 11 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.904C>T	p.Leu302Phe	missense	Exon 11 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.904C>T	p.Leu302Phe	missense	Exon 12 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.00976 AC: 1485 AN: 152192 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00271 AC: 677 AN: 249460 AF XY: 0.00213

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.000701

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00108 AC: 1573 AN: 1461282 Hom.: 29 Cov.: 33 AF XY: 0.000896 AC XY: 651 AN XY: 726966

African (AFR) AF: 0.0358 AC: 1198 AN: 33474

American (AMR) AF: 0.00237 AC: 106 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52990

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5720

European-Non Finnish (NFE) AF: 0.0000800 AC: 89 AN: 1111956

Other (OTH) AF: 0.00257 AC: 155 AN: 60378

GnomAD4 genome AF: 0.00980 AC: 1492 AN: 152310 Hom.: 24 Cov.: 32 AF XY: 0.00967 AC XY: 720 AN XY: 74478

African (AFR) AF: 0.0339 AC: 1408 AN: 41564

American (AMR) AF: 0.00307 AC: 47 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68014

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00224 Hom.: 7

Bravo AF: 0.0118

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00325 AC: 394

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial hemophagocytic lymphohistiocytosis 3 (3)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not provided (1)
-	-	1	UNC13D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.28	N
PhyloP100		2.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.062
Sift	Benign	0.58	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.083
MVP		0.60
MPC		0.11
ClinPred		0.00071	T
GERP RS		3.4
Varity_R		0.039
gMVP		0.15
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs55661958; hg19: chr17-73836146; COSMIC: COSV104392535;