rs142996967

Variant names:

• chr17-75843090-C-T
• rs142996967
• NM_199242.3:c.262-17G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-75843090-C-T
• chr17-75843090-C-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.262-17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 673,414 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (89 hom., cov: 32)
  • Exomes 𝑓: 0.012 (133 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.39
• 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=-0.86).
• BP6: Variant 17-75843090-C-T is Benign according to our data. Variant chr17-75843090-C-T is described in ClinVar as Benign. ClinVar VariationId is 263230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0621 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.262-17G>A		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.262-17G>A		intron	N/A	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.262-17G>A		intron	N/A	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.262-17G>A		intron	N/A	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3105 AN: 139318 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.00276

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.0179

Gnomad FIN AF: 0.000714

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.000806

Gnomad OTH AF: 0.0178

GnomAD2 exomes AF: 0.0130 AC: 3138 AN: 241030 AF XY: 0.0110

Gnomad AFR exome AF: 0.0669

Gnomad AMR exome AF: 0.0314

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.0272

Gnomad FIN exome AF: 0.000793

Gnomad NFE exome AF: 0.000845

Gnomad OTH exome AF: 0.00830

GnomAD4 exome AF: 0.0118 AC: 6314 AN: 533964 Hom.: 133 Cov.: 26 AF XY: 0.0107 AC XY: 3107 AN XY: 289386

African (AFR) AF: 0.121 AC: 2049 AN: 16948

American (AMR) AF: 0.0362 AC: 1367 AN: 37808

Ashkenazi Jewish (ASJ) AF: 0.00455 AC: 67 AN: 14718

East Asian (EAS) AF: 0.0280 AC: 698 AN: 24902

South Asian (SAS) AF: 0.0156 AC: 1092 AN: 70158

European-Finnish (FIN) AF: 0.00159 AC: 47 AN: 29552

Middle Eastern (MID) AF: 0.0131 AC: 42 AN: 3204

European-Non Finnish (NFE) AF: 0.00140 AC: 436 AN: 312534

Other (OTH) AF: 0.0214 AC: 516 AN: 24140

GnomAD4 genome AF: 0.0223 AC: 3110 AN: 139450 Hom.: 89 Cov.: 32 AF XY: 0.0221 AC XY: 1494 AN XY: 67586

African (AFR) AF: 0.0642 AC: 2524 AN: 39292

American (AMR) AF: 0.0198 AC: 283 AN: 14294

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 9 AN: 3262

East Asian (EAS) AF: 0.0328 AC: 132 AN: 4030

South Asian (SAS) AF: 0.0181 AC: 68 AN: 3760

European-Finnish (FIN) AF: 0.000714 AC: 6 AN: 8398

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.000806 AC: 51 AN: 63304

Other (OTH) AF: 0.0181 AC: 36 AN: 1992

Alfa AF: 0.0101 Hom.: 12

Bravo AF: 0.0246

Asia WGS AF: 0.0230 AC: 78 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.73
DANN	Benign	0.57
PhyloP100		-2.4
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: rs142996967; hg19: chr17-73839171; COSMIC: COSV104368787;