NM_199242.3:c.1992+5G>A

Variant names:

• chr17-75834915-C-T
• rs17581728
• NM_199242.3:c.1992+5G>A

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.1992+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,613,612 control chromosomes in the GnomAD database, including 38,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2989 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35476 hom.)
• Consequence: UNC13D NM_199242.3 splice_region, intron
• Scores: Splicing: ADA: 0.9297
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.241
• Publications: 21 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=-0.82).
• BP6: Variant 17-75834915-C-T is Benign according to our data. Variant chr17-75834915-C-T is described in ClinVar as Benign. ClinVar VariationId is 263222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 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.1992+5G>A		splice_region 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.1992+5G>A		splice_region intron	N/A	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.1992+5G>A		splice_region intron	N/A	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.1992+5G>A		splice_region intron	N/A	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29309 AN: 151854 Hom.: 2980 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.0925

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.197

GnomAD2 exomes AF: 0.189 AC: 47583 AN: 251306 AF XY: 0.193

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.0860

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.217 AC: 317337 AN: 1461640 Hom.: 35476 Cov.: 40 AF XY: 0.217 AC XY: 157554 AN XY: 727126

African (AFR) AF: 0.148 AC: 4940 AN: 33474

American (AMR) AF: 0.138 AC: 6156 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5666 AN: 26134

East Asian (EAS) AF: 0.0933 AC: 3704 AN: 39698

South Asian (SAS) AF: 0.185 AC: 15974 AN: 86252

European-Finnish (FIN) AF: 0.178 AC: 9500 AN: 53232

Middle Eastern (MID) AF: 0.191 AC: 1098 AN: 5762

European-Non Finnish (NFE) AF: 0.232 AC: 257586 AN: 1111974

Other (OTH) AF: 0.211 AC: 12713 AN: 60390

GnomAD4 genome AF: 0.193 AC: 29331 AN: 151972 Hom.: 2989 Cov.: 32 AF XY: 0.188 AC XY: 13994 AN XY: 74252

African (AFR) AF: 0.154 AC: 6393 AN: 41404

American (AMR) AF: 0.161 AC: 2457 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 709 AN: 3470

East Asian (EAS) AF: 0.0931 AC: 482 AN: 5176

South Asian (SAS) AF: 0.169 AC: 816 AN: 4820

European-Finnish (FIN) AF: 0.179 AC: 1888 AN: 10566

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15880 AN: 67960

Other (OTH) AF: 0.204 AC: 431 AN: 2112

Alfa AF: 0.219 Hom.: 9600

Bravo AF: 0.191

Asia WGS AF: 0.164 AC: 568 AN: 3478

EpiCase AF: 0.240

EpiControl AF: 0.240

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial hemophagocytic lymphohistiocytosis 3 (3)
-	-	3	not specified (3)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.51
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17581728; hg19: chr17-73830996; COSMIC: COSV52883727; COSMIC: COSV52883727;