rs201930023

Variant names:

• chr17-75831238-G-C
• rs201930023
• NM_199242.3:c.2553+5C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_199242.3(UNC13D):​c.2553+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,614,130 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: UNC13D NM_199242.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004334
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -1.90
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302174 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-75831238-G-C is Benign according to our data. Variant chr17-75831238-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533109.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000656 (100/152326) while in subpopulation EAS AF = 0.0104 (54/5176). AF 95% confidence interval is 0.00821. There are 3 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.2553+5C>G		splice_region 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.2553+5C>G		splice_region intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.2553+5C>G		splice_region intron	N/A	ENSP00000388093.1
	UNC13D	ENST00000868100.1		c.2553+5C>G		splice_region intron	N/A	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152208 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000918 AC: 230 AN: 250480 AF XY: 0.000870

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000278 AC: 406 AN: 1461804 Hom.: 3 Cov.: 34 AF XY: 0.000257 AC XY: 187 AN XY: 727196

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00645 AC: 256 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111994

Other (OTH) AF: 0.00167 AC: 101 AN: 60394

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152326 Hom.: 3 Cov.: 33 AF XY: 0.000765 AC XY: 57 AN XY: 74490

African (AFR) AF: 0.000842 AC: 35 AN: 41574

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0104 AC: 54 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000299 Hom.: 1

Bravo AF: 0.000680

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Familial hemophagocytic lymphohistiocytosis 3 (3)
-	-	3	not provided (3)
-	-	1	UNC13D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.039
DANN	Benign	0.73
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.014
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: rs201930023; hg19: chr17-73827319;