rs3744026

Variant names:

• chr17-75835819-T-C
• rs3744026
• NM_199242.3:c.1596+36A>G

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.1596+36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,888 control chromosomes in the GnomAD database, including 21,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (7932 hom., cov: 33)
  • Exomes 𝑓: 0.094 (13430 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.92
• Publications: 18 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, ClinGen, 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=-0.98).
• BP6: Variant 17-75835819-T-C is Benign according to our data. Variant chr17-75835819-T-C is described in ClinVar as Benign. ClinVar VariationId is 263215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.58 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.1596+36A>G		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.1596+36A>G		intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000412096.6	TSL:2	c.1596+36A>G		intron	N/A	ENSP00000388093.1
	UNC13D	ENST00000868100.1		c.1596+36A>G		intron	N/A	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35095 AN: 152084 Hom.: 7907 Cov.: 33

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.0531

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.0684

Gnomad OTH AF: 0.207

GnomAD2 exomes AF: 0.141 AC: 35467 AN: 251240 AF XY: 0.134

Gnomad AFR exome AF: 0.605

Gnomad AMR exome AF: 0.0942

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.0511

Gnomad NFE exome AF: 0.0699

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.0938 AC: 137126 AN: 1461686 Hom.: 13430 Cov.: 35 AF XY: 0.0948 AC XY: 68923 AN XY: 727126

African (AFR) AF: 0.605 AC: 20249 AN: 33480

American (AMR) AF: 0.0989 AC: 4425 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 4081 AN: 26136

East Asian (EAS) AF: 0.338 AC: 13436 AN: 39700

South Asian (SAS) AF: 0.152 AC: 13100 AN: 86258

European-Finnish (FIN) AF: 0.0536 AC: 2851 AN: 53220

Middle Eastern (MID) AF: 0.250 AC: 1442 AN: 5768

European-Non Finnish (NFE) AF: 0.0626 AC: 69597 AN: 1112006

Other (OTH) AF: 0.132 AC: 7945 AN: 60394

GnomAD4 genome AF: 0.231 AC: 35163 AN: 152202 Hom.: 7932 Cov.: 33 AF XY: 0.228 AC XY: 17002 AN XY: 74412

African (AFR) AF: 0.586 AC: 24345 AN: 41510

American (AMR) AF: 0.131 AC: 2009 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 621 AN: 3470

East Asian (EAS) AF: 0.330 AC: 1706 AN: 5164

South Asian (SAS) AF: 0.155 AC: 751 AN: 4830

European-Finnish (FIN) AF: 0.0531 AC: 564 AN: 10620

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.0684 AC: 4651 AN: 67988

Other (OTH) AF: 0.205 AC: 433 AN: 2116

Alfa AF: 0.124 Hom.: 3062

Bravo AF: 0.254

Asia WGS AF: 0.233 AC: 809 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.23
DANN	Benign	0.25
PhyloP100		-2.9
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: rs3744026; hg19: chr17-73831900; COSMIC: COSV52883523; COSMIC: COSV52883523;