rs747308306

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020919.4(ALS2):​c.3449T>C​(p.Met1150Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

ALS2
NM_020919.4 missense

Scores

2
7
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.10
Variant links:
Genes affected
ALS2 (HGNC:443): (alsin Rho guanine nucleotide exchange factor ALS2) The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALS2NM_020919.4 linkc.3449T>C p.Met1150Thr missense_variant Exon 21 of 34 ENST00000264276.11 NP_065970.2 Q96Q42-1A8K4R4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALS2ENST00000264276.11 linkc.3449T>C p.Met1150Thr missense_variant Exon 21 of 34 1 NM_020919.4 ENSP00000264276.6 Q96Q42-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000827
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Benign
-0.0038
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
T
Eigen
Benign
0.076
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.0075
T
MetaRNN
Uncertain
0.57
D
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.57
N
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.3
N
REVEL
Benign
0.27
Sift
Uncertain
0.0090
D
Sift4G
Uncertain
0.0090
D
Polyphen
0.12
B
Vest4
0.71
MutPred
0.44
Loss of stability (P = 0.028);
MVP
0.68
MPC
0.32
ClinPred
0.83
D
GERP RS
5.9
Varity_R
0.29
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.30
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.30
Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747308306; hg19: chr2-202589081; API