rs373551579

Variant names:

• chr17-75842558-C-T
• rs373551579
• NM_199242.3:c.444G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_199242.3(UNC13D):​c.444G>A​(p.Gly148Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,611,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.793
• 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, ClinGen, Labcorp Genetics (formerly Invitae)
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-75842558-C-T is Benign according to our data. Variant chr17-75842558-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 325272.
• BP7: Synonymous conserved (PhyloP=-0.793 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000322 (49/152352) while in subpopulation AMR AF = 0.00144 (22/15308). AF 95% confidence interval is 0.000972. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.444G>A	p.Gly148Gly	synonymous	Exon 6 of 32	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.444G>A	p.Gly148Gly	synonymous	Exon 6 of 32	ENSP00000207549.3	Q70J99-1
	UNC13D	ENST00000412096.6	TSL:2	c.444G>A	p.Gly148Gly	synonymous	Exon 6 of 33	ENSP00000388093.1	Q70J99-3
	UNC13D	ENST00000868100.1		c.444G>A	p.Gly148Gly	synonymous	Exon 7 of 33	ENSP00000538159.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000197 AC: 49 AN: 248742 AF XY: 0.000171

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000268

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000283 AC: 413 AN: 1459342 Hom.: 0 Cov.: 32 AF XY: 0.000271 AC XY: 197 AN XY: 725724

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.000314 AC: 14 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86116

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.000326 AC: 362 AN: 1111078

Other (OTH) AF: 0.000199 AC: 12 AN: 60312

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74496

African (AFR) AF: 0.0000721 AC: 3 AN: 41586

American (AMR) AF: 0.00144 AC: 22 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000499

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Familial hemophagocytic lymphohistiocytosis 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.4
DANN	Benign	0.77
PhyloP100		-0.79
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs373551579; hg19: chr17-73838639;