rs112501005

Variant names:

• chr17-75836294-A-G
• rs112501005
• NM_199242.3:c.1390-38T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_199242.3(UNC13D):​c.1390-38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,613,048 control chromosomes in the GnomAD database, including 605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (69 hom., cov: 33)
  • Exomes 𝑓: 0.025 (536 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.710
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-75836294-A-G is Benign according to our data. Variant chr17-75836294-A-G is described in ClinVar as [Benign]. Clinvar id is 263213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.028 (4270/152306) while in subpopulation AFR AF = 0.0433 (1801/41568). AF 95% confidence interval is 0.0417. There are 69 homozygotes in GnomAd4. There are 1940 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 69 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.1390-38T>C		intron_variant	Intron 15 of 31	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.1390-38T>C		intron_variant	Intron 15 of 31	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4252 AN: 152188 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.00649

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0227 AC: 5633 AN: 247868 AF XY: 0.0231

Gnomad AFR exome AF: 0.0433

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00576

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0247

GnomAD4 exome AF: 0.0254 AC: 37145 AN: 1460742 Hom.: 536 Cov.: 40 AF XY: 0.0253 AC XY: 18403 AN XY: 726584

African (AFR) AF: 0.0384 AC: 1287 AN: 33476

American (AMR) AF: 0.0189 AC: 844 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.0376 AC: 979 AN: 26066

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.0259 AC: 2234 AN: 86112

European-Finnish (FIN) AF: 0.00724 AC: 384 AN: 53016

Middle Eastern (MID) AF: 0.0257 AC: 148 AN: 5764

European-Non Finnish (NFE) AF: 0.0268 AC: 29787 AN: 1111674

Other (OTH) AF: 0.0245 AC: 1480 AN: 60356

GnomAD4 genome AF: 0.0280 AC: 4270 AN: 152306 Hom.: 69 Cov.: 33 AF XY: 0.0261 AC XY: 1940 AN XY: 74472

African (AFR) AF: 0.0433 AC: 1801 AN: 41568

American (AMR) AF: 0.0205 AC: 314 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0265 AC: 128 AN: 4824

European-Finnish (FIN) AF: 0.00649 AC: 69 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0255 AC: 1734 AN: 68014

Other (OTH) AF: 0.0369 AC: 78 AN: 2114

Alfa AF: 0.0270 Hom.: 12

Bravo AF: 0.0297

Asia WGS AF: 0.0120 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.44
PhyloP100		-0.71
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: rs112501005; hg19: chr17-73832375; COSMIC: COSV104392600;