rs185419295

Variant names:

• chr17-75839792-G-A
• rs185419295
• NM_199242.3:c.1055+47C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-75839792-G-A
• chr17-75839792-G-T

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.1055+47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,595,664 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (65 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.18
• Publications: 0 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=-0.85).
• BP6: Variant 17-75839792-G-A is Benign according to our data. Variant chr17-75839792-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 263209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00563 (857/152290) while in subpopulation NFE AF = 0.00938 (638/68022). AF 95% confidence interval is 0.00878. There are 7 homozygotes in GnomAd4. There are 416 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.1055+47C>T		intron_variant	Intron 12 of 31	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.1055+47C>T		intron_variant	Intron 12 of 31	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 856 AN: 152172 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00936

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00662 AC: 1642 AN: 248006 AF XY: 0.00688

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00602

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00677

GnomAD4 exome AF: 0.00845 AC: 12199 AN: 1443374 Hom.: 65 Cov.: 29 AF XY: 0.00836 AC XY: 6010 AN XY: 718832

African (AFR) AF: 0.000635 AC: 21 AN: 33080

American (AMR) AF: 0.00213 AC: 95 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26026

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39602

South Asian (SAS) AF: 0.00646 AC: 555 AN: 85894

European-Finnish (FIN) AF: 0.00719 AC: 373 AN: 51896

Middle Eastern (MID) AF: 0.00357 AC: 20 AN: 5602

European-Non Finnish (NFE) AF: 0.00975 AC: 10692 AN: 1096858

Other (OTH) AF: 0.00675 AC: 403 AN: 59720

GnomAD4 genome AF: 0.00563 AC: 857 AN: 152290 Hom.: 7 Cov.: 32 AF XY: 0.00559 AC XY: 416 AN XY: 74472

African (AFR) AF: 0.00171 AC: 71 AN: 41554

American (AMR) AF: 0.00262 AC: 40 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4826

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00938 AC: 638 AN: 68022

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00570 Hom.: 0

Bravo AF: 0.00493

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely 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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	-0.85
CADD	Benign	0.12
DANN	Benign	0.80
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

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: rs185419295; hg19: chr17-73835873; COSMIC: COSV99256546; COSMIC: COSV99256546;