NM_001080421.3:c.4855G>A

Variant names:

• chr19-17606311-C-T
• rs779007137
• NM_001080421.3:c.4855G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001080421.3(UNC13A):​c.4855G>A​(p.Val1619Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 1,549,630 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (1 hom.)
• Consequence: UNC13A NM_001080421.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.47
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07250783).

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.4855G>A	p.Val1619Met	missense	Exon 44 of 44	NP_001073890.2	Q9UPW8
	UNC13A	NM_001387021.1		c.4843G>A	p.Val1615Met	missense	Exon 42 of 42	NP_001373950.1
	UNC13A	NM_001387022.1		c.4840G>A	p.Val1614Met	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.4855G>A	p.Val1619Met	missense	Exon 44 of 44	ENSP00000429562.2	Q9UPW8
	UNC13A	ENST00000551649.5	TSL:5	c.4912G>A	p.Val1638Met	missense	Exon 45 of 45	ENSP00000447236.1	F8W059
	UNC13A	ENST00000552293.5	TSL:5	c.4837G>A	p.Val1613Met	missense	Exon 42 of 42	ENSP00000447572.1	F8W0P6

Frequencies

GnomAD3 genomes AF: 0.000479 AC: 73 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000436 AC: 63 AN: 144656 AF XY: 0.000447

Gnomad AFR exome AF: 0.000282

Gnomad AMR exome AF: 0.0000403

Gnomad ASJ exome AF: 0.000241

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000803

Gnomad NFE exome AF: 0.000832

Gnomad OTH exome AF: 0.000712

GnomAD4 exome AF: 0.000651 AC: 909 AN: 1397266 Hom.: 1 Cov.: 31 AF XY: 0.000647 AC XY: 446 AN XY: 689578

African (AFR) AF: 0.000222 AC: 7 AN: 31492

American (AMR) AF: 0.0000834 AC: 3 AN: 35980

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 35768

South Asian (SAS) AF: 0.00 AC: 0 AN: 79392

European-Finnish (FIN) AF: 0.00128 AC: 59 AN: 46054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.000741 AC: 800 AN: 1079712

Other (OTH) AF: 0.000620 AC: 36 AN: 58042

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74516

African (AFR) AF: 0.0000962 AC: 4 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68034

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000630 Hom.: 0

Bravo AF: 0.000393

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000342 AC: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	UNC13A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Benign	0.091	T
Sift4G	Uncertain	0.056	T
Polyphen		0.45	B
Vest4		0.32
MVP		0.16
MPC		1.6
ClinPred		0.085	T
GERP RS		3.0
Varity_R		0.21
gMVP		0.54
Mutation Taster		=61/39	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: rs779007137; hg19: chr19-17717120; COSMIC: COSV53203335; COSMIC: COSV53203335;