19-17606229-C-T

Variant names:

• chr19-17606229-C-T
• rs1417486551
• NM_001080421.3:c.4937G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080421.3(UNC13A):​c.4937G>A​(p.Arg1646His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,551,012 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: UNC13A NM_001080421.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.861
• Publications: 1 publications found

Genes affected

UNC13A (HGNC:23150): (unc-13 homolog A) This gene encodes a member of the UNC13 family. UNC13 proteins bind to phorbol esters and diacylglycerol and play important roles in neurotransmitter release at synapses. Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis. [provided by RefSeq, Feb 2012]

UNC13A Gene-Disease associations (from GenCC):

• congenital nervous system disorder

  Inheritance: Unknown Classification: LIMITED Submitted by: Illumina, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12040368).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080421.3. 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
	UNC13A	NM_001080421.3	MANE Select	c.4937G>A	p.Arg1646His	missense	Exon 44 of 44	NP_001073890.2	Q9UPW8
	UNC13A	NM_001387021.1		c.4925G>A	p.Arg1642His	missense	Exon 42 of 42	NP_001373950.1
	UNC13A	NM_001387022.1		c.4922G>A	p.Arg1641His	missense	Exon 42 of 42	NP_001373951.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13A	ENST00000519716.7	TSL:5 MANE Select	c.4937G>A	p.Arg1646His	missense	Exon 44 of 44	ENSP00000429562.2	Q9UPW8
	UNC13A	ENST00000551649.5	TSL:5	c.4994G>A	p.Arg1665His	missense	Exon 45 of 45	ENSP00000447236.1	F8W059
	UNC13A	ENST00000552293.5	TSL:5	c.4919G>A	p.Arg1640His	missense	Exon 42 of 42	ENSP00000447572.1	F8W0P6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000206 AC: 3 AN: 145742 AF XY: 0.0000377

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000549

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000114 AC: 16 AN: 1398756 Hom.: 0 Cov.: 31 AF XY: 0.0000145 AC XY: 10 AN XY: 690542

African (AFR) AF: 0.00 AC: 0 AN: 30776

American (AMR) AF: 0.00 AC: 0 AN: 36108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25124

East Asian (EAS) AF: 0.00 AC: 0 AN: 35418

South Asian (SAS) AF: 0.00 AC: 0 AN: 79520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 0.0000148 AC: 16 AN: 1080574

Other (OTH) AF: 0.00 AC: 0 AN: 57968

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.86
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.060
Sift	Benign	0.036	D
Sift4G	Uncertain	0.049	D
Polyphen		0.16	B
Vest4		0.16
MutPred		0.48		Loss of methylation at R1646 (P = 0.0447)
MVP		0.13
MPC		1.7
ClinPred		0.64	D
GERP RS		3.0
Varity_R		0.20
gMVP		0.41
Mutation Taster		=87/13	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: rs1417486551; hg19: chr19-17717038;