19-17606244-C-A

Variant names:

• chr19-17606244-C-A
• rs745598504
• NM_001080421.3:c.4922G>T

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.4922G>T​(p.Arg1641Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,396,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1641H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UNC13A NM_001080421.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 0 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=0.189073).

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.4922G>T	p.Arg1641Leu	missense	Exon 44 of 44	NP_001073890.2	Q9UPW8
	UNC13A	NM_001387021.1		c.4910G>T	p.Arg1637Leu	missense	Exon 42 of 42	NP_001373950.1
	UNC13A	NM_001387022.1		c.4907G>T	p.Arg1636Leu	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.4922G>T	p.Arg1641Leu	missense	Exon 44 of 44	ENSP00000429562.2	Q9UPW8
	UNC13A	ENST00000551649.5	TSL:5	c.4979G>T	p.Arg1660Leu	missense	Exon 45 of 45	ENSP00000447236.1	F8W059
	UNC13A	ENST00000552293.5	TSL:5	c.4904G>T	p.Arg1635Leu	missense	Exon 42 of 42	ENSP00000447572.1	F8W0P6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396164 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688884

African (AFR) AF: 0.00 AC: 0 AN: 30824

American (AMR) AF: 0.00 AC: 0 AN: 35852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25096

East Asian (EAS) AF: 0.00 AC: 0 AN: 35352

South Asian (SAS) AF: 0.00 AC: 0 AN: 79318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078790

Other (OTH) AF: 0.00 AC: 0 AN: 57892

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.62	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.065
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.016	D
Polyphen		0.015	B
Vest4		0.40
MutPred		0.49		Loss of MoRF binding (P = 0.0747)
MVP		0.11
MPC		1.1
ClinPred		0.94	D
GERP RS		1.9
Varity_R		0.34
gMVP		0.63
Mutation Taster		=85/15	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: rs745598504; hg19: chr19-17717053;