NM_199242.3:c.2299-46C>T

Variant names:

• chr17-75834189-G-A
• rs7212635
• NM_199242.3:c.2299-46C>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.2299-46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0954 in 1,609,286 control chromosomes in the GnomAD database, including 14,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4394 hom., cov: 33)
  • Exomes 𝑓: 0.086 (9908 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.109
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-75834189-G-A is Benign according to our data. Variant chr17-75834189-G-A is described in ClinVar as Benign. ClinVar VariationId is 263225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.417 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.2299-46C>T		intron	N/A	NP_954712.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.2299-46C>T		intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.2299-46C>T		intron	N/A	ENSP00000388093.1
	UNC13D	ENST00000868100.1		c.2299-46C>T		intron	N/A	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27528 AN: 152046 Hom.: 4384 Cov.: 33

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.0663

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.125 AC: 30371 AN: 242050 AF XY: 0.121

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.0805

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0680

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0865 AC: 125969 AN: 1457122 Hom.: 9908 Cov.: 33 AF XY: 0.0878 AC XY: 63610 AN XY: 724634

African (AFR) AF: 0.443 AC: 14784 AN: 33380

American (AMR) AF: 0.0846 AC: 3743 AN: 44250

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3235 AN: 26070

East Asian (EAS) AF: 0.338 AC: 13371 AN: 39524

South Asian (SAS) AF: 0.144 AC: 12355 AN: 85804

European-Finnish (FIN) AF: 0.0537 AC: 2787 AN: 51910

Middle Eastern (MID) AF: 0.219 AC: 1261 AN: 5754

European-Non Finnish (NFE) AF: 0.0608 AC: 67526 AN: 1110202

Other (OTH) AF: 0.115 AC: 6907 AN: 60228

GnomAD4 genome AF: 0.181 AC: 27570 AN: 152164 Hom.: 4394 Cov.: 33 AF XY: 0.181 AC XY: 13461 AN XY: 74398

African (AFR) AF: 0.423 AC: 17529 AN: 41488

American (AMR) AF: 0.107 AC: 1630 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 494 AN: 3470

East Asian (EAS) AF: 0.329 AC: 1702 AN: 5168

South Asian (SAS) AF: 0.148 AC: 714 AN: 4822

European-Finnish (FIN) AF: 0.0525 AC: 557 AN: 10606

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0663 AC: 4506 AN: 68014

Other (OTH) AF: 0.170 AC: 358 AN: 2110

Alfa AF: 0.104 Hom.: 1140

Bravo AF: 0.198

Asia WGS AF: 0.218 AC: 758 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.89
PhyloP100		-0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7212635; hg19: chr17-73830270; COSMIC: COSV52882856; COSMIC: COSV52882856;