5-122444636-G-T

Variant names:

• chr5-122444636-G-T
• rs373891275
• NM_005460.4:c.1496G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005460.4(SNCAIP):​c.1496G>T​(p.Arg499Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R499Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SNCAIP NM_005460.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.81
• Publications: 0 publications found

Genes affected

SNCAIP (HGNC:11139): (synuclein alpha interacting protein) This gene encodes a protein containing several protein-protein interaction domains, including ankyrin-like repeats, a coiled-coil domain, and an ATP/GTP-binding motif. The encoded protein interacts with alpha-synuclein in neuronal tissue and may play a role in the formation of cytoplasmic inclusions and neurodegeneration. A mutation in this gene has been associated with Parkinson's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

MGC32805 (HGNC:28478):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005460.4. 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
	SNCAIP	NM_005460.4	MANE Select	c.1496G>T	p.Arg499Leu	missense	Exon 8 of 11	NP_005451.2	Q9Y6H5-1
	SNCAIP	NM_001308100.2		c.1637G>T	p.Arg546Leu	missense	Exon 10 of 14	NP_001295029.1	Q9Y6H5-3
	SNCAIP	NM_001308105.1		c.1316G>T	p.Arg439Leu	missense	Exon 6 of 9	NP_001295034.1	B7Z995

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCAIP	ENST00000261368.13	TSL:1 MANE Select	c.1496G>T	p.Arg499Leu	missense	Exon 8 of 11	ENSP00000261368.8	Q9Y6H5-1
	SNCAIP	ENST00000261367.11	TSL:1	c.1637G>T	p.Arg546Leu	missense	Exon 10 of 14	ENSP00000261367.7	Q9Y6H5-3
	SNCAIP	ENST00000508017.5	TSL:1	n.*243G>T		non_coding_transcript_exon	Exon 6 of 9	ENSP00000424338.1	Q6L982

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111922

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.64	N
PhyloP100		5.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.020	D
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.75
MutPred		0.39		Loss of disorder (P = 0.0654)
MVP		0.88
MPC		0.86
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.49
gMVP		0.69
Mutation Taster		=24/76	disease causing

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: rs373891275; hg19: chr5-121780331; COSMIC: COSV54410381; COSMIC: COSV54410381;