17-75840005-A-C

Variant names:

• chr17-75840005-A-C
• rs140758914
• NM_199242.3:c.951+13T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199242.3(UNC13D):​c.951+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,498 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (51 hom., cov: 32)
  • Exomes 𝑓: 0.018 (456 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.323
• Publications: 2 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 (BayesDel_noAF=-0.83).
• BP6: Variant 17-75840005-A-C is Benign according to our data. Variant chr17-75840005-A-C is described in ClinVar as Benign. ClinVar VariationId is 263248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

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.951+13T>G		intron	N/A	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.951+13T>G		intron	N/A	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.951+13T>G		intron	N/A	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.951+13T>G		intron	N/A	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2582 AN: 152230 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0744

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0187 AC: 4654 AN: 249368 AF XY: 0.0202

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0637

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.00136

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0263

GnomAD4 exome AF: 0.0183 AC: 26705 AN: 1461150 Hom.: 456 Cov.: 33 AF XY: 0.0190 AC XY: 13802 AN XY: 726898

African (AFR) AF: 0.0159 AC: 531 AN: 33474

American (AMR) AF: 0.0177 AC: 793 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 1638 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0250 AC: 2159 AN: 86248

European-Finnish (FIN) AF: 0.00193 AC: 102 AN: 52932

Middle Eastern (MID) AF: 0.133 AC: 760 AN: 5730

European-Non Finnish (NFE) AF: 0.0173 AC: 19268 AN: 1111890

Other (OTH) AF: 0.0241 AC: 1453 AN: 60374

GnomAD4 genome AF: 0.0169 AC: 2578 AN: 152348 Hom.: 51 Cov.: 32 AF XY: 0.0163 AC XY: 1215 AN XY: 74504

African (AFR) AF: 0.0126 AC: 525 AN: 41590

American (AMR) AF: 0.0195 AC: 299 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0744 AC: 258 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0271 AC: 131 AN: 4828

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10624

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1226 AN: 68022

Other (OTH) AF: 0.0327 AC: 69 AN: 2112

Alfa AF: 0.0189 Hom.: 63

Bravo AF: 0.0186

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.83
CADD	Benign	4.4
DANN	Benign	0.46
PhyloP100		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140758914; hg19: chr17-73836086; COSMIC: COSV104392536;