19-17606221-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001080421.3(UNC13A):c.4945G>C(p.Ala1649Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000714 in 1,399,772 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: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: UNC13A NM_001080421.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UNC13A
• BP4: Computational evidence support a benign effect (MetaRNN=0.3598528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13A	NM_001080421.3	c.4945G>C	p.Ala1649Pro	missense_variant	44/44	ENST00000519716.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13A	ENST00000519716.7	c.4945G>C	p.Ala1649Pro	missense_variant	44/44	5	NM_001080421.3	A2
UNC13A	ENST00000551649.5	c.5002G>C	p.Ala1668Pro	missense_variant	45/45	5		P3
UNC13A	ENST00000552293.5	c.4927G>C	p.Ala1643Pro	missense_variant	42/42	5		A2
UNC13A	ENST00000550896.1	c.4864G>C	p.Ala1622Pro	missense_variant	40/40	5		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399772 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The c.4945G>C (p.A1649P) alteration is located in exon 44 (coding exon 44) of the UNC13A gene. This alteration results from a G to C substitution at nucleotide position 4945, causing the alanine (A) at amino acid position 1649 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.90	L;.;.;.
MutationTaster	Benign	0.63	N;N;N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.096	T;D;T;T
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.41	B;.;.;.
Vest4		0.30
MutPred		0.57		Loss of catalytic residue at A1649 (P = 0.0056);.;.;.;
MVP		0.49
MPC		1.7
ClinPred		0.88	D
GERP RS		1.8
Varity_R		0.40
gMVP		0.56

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-17717030;