17-75840360-G-A

Variant names:

• chr17-75840360-G-A
• rs7226310
• NM_199242.3:c.754-31C>T

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.754-31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0539 in 1,610,762 control chromosomes in the GnomAD database, including 3,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (1238 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2722 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.41
• 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, 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=-0.89).
• BP6: Variant 17-75840360-G-A is Benign according to our data. Variant chr17-75840360-G-A is described in ClinVar as Benign. ClinVar VariationId is 263244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 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.754-31C>T		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.754-31C>T		intron	N/A	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000965711.1		c.761C>T	p.Thr254Met	missense	Exon 11 of 33	ENSP00000635770.1
	UNC13D	ENST00000412096.6	TSL:2	c.754-31C>T		intron	N/A	ENSP00000388093.1	Q70J99-3

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14549 AN: 152020 Hom.: 1232 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.0264

Gnomad SAS AF: 0.0831

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0851

GnomAD2 exomes AF: 0.0579 AC: 14312 AN: 246982 AF XY: 0.0580

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.0463

Gnomad EAS exome AF: 0.0268

Gnomad FIN exome AF: 0.0340

Gnomad NFE exome AF: 0.0433

Gnomad OTH exome AF: 0.0534

GnomAD4 exome AF: 0.0495 AC: 72199 AN: 1458626 Hom.: 2722 Cov.: 34 AF XY: 0.0505 AC XY: 36663 AN XY: 725652

African (AFR) AF: 0.238 AC: 7952 AN: 33398

American (AMR) AF: 0.0305 AC: 1359 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 1203 AN: 26092

East Asian (EAS) AF: 0.0375 AC: 1489 AN: 39658

South Asian (SAS) AF: 0.0912 AC: 7858 AN: 86122

European-Finnish (FIN) AF: 0.0356 AC: 1883 AN: 52886

Middle Eastern (MID) AF: 0.0725 AC: 393 AN: 5422

European-Non Finnish (NFE) AF: 0.0419 AC: 46569 AN: 1110208

Other (OTH) AF: 0.0580 AC: 3493 AN: 60254

GnomAD4 genome AF: 0.0958 AC: 14575 AN: 152136 Hom.: 1238 Cov.: 32 AF XY: 0.0948 AC XY: 7052 AN XY: 74388

African (AFR) AF: 0.225 AC: 9339 AN: 41462

American (AMR) AF: 0.0554 AC: 846 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0542 AC: 188 AN: 3470

East Asian (EAS) AF: 0.0264 AC: 137 AN: 5180

South Asian (SAS) AF: 0.0835 AC: 403 AN: 4824

European-Finnish (FIN) AF: 0.0340 AC: 361 AN: 10612

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0456 AC: 3097 AN: 67986

Other (OTH) AF: 0.0837 AC: 177 AN: 2114

Alfa AF: 0.0721 Hom.: 232

Bravo AF: 0.102

Asia WGS AF: 0.0620 AC: 218 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.59
DANN	Benign	0.76
PhyloP100		-1.4
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)		0.010		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: rs7226310; hg19: chr17-73836441; COSMIC: COSV52884447; COSMIC: COSV52884447;