3-45722049-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014016.5(SACM1L):ā€‹c.729T>Gā€‹(p.Ile243Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

SACM1L
NM_014016.5 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.642
Variant links:
Genes affected
SACM1L (HGNC:17059): (SAC1 like phosphatidylinositide phosphatase) This gene encodes an integral membrane protein, which is localized to the endoplasmic reticulum, and functions as a phosphoinositide phosphatase that hydrolyzes phosphatidylinositol 3-phosphate, phosphatidylinositol 4-phosphate, and phosphatidylinositol 3,5-bisphosphate. Deletion of this gene in mouse results in preimplantation lethality. Other studies suggest that this gene is also involved in the organization of golgi membranes and mitotic spindles. Alternatively spliced transcript variants have been found for this gene. A C-terminally extended isoform is also predicted to be produced by the use of an alternative in-frame, downstream translation termination codon via a stop codon readthrough mechanism.[provided by RefSeq, Dec 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SACM1LNM_014016.5 linkc.729T>G p.Ile243Met missense_variant 9/20 ENST00000389061.10 NP_054735.3 Q9NTJ5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SACM1LENST00000389061.10 linkc.729T>G p.Ile243Met missense_variant 9/201 NM_014016.5 ENSP00000373713.4 Q9NTJ5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000280
AC:
7
AN:
250290
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135320
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000147
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460726
Hom.:
0
Cov.:
29
AF XY:
0.00000413
AC XY:
3
AN XY:
726620
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000151
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 10, 2023The c.729T>G (p.I243M) alteration is located in exon 9 (coding exon 9) of the SACM1L gene. This alteration results from a T to G substitution at nucleotide position 729, causing the isoleucine (I) at amino acid position 243 to be replaced by a methionine (M). 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
Benign
0.13
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
15
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
.;T
Eigen
Benign
-0.12
Eigen_PC
Benign
-0.36
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.85
D;D
M_CAP
Benign
0.027
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Benign
-0.55
T
MutationAssessor
Uncertain
2.9
.;M
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-2.3
N;N
REVEL
Uncertain
0.43
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0080
D;D
Polyphen
1.0
.;D
Vest4
0.60
MutPred
0.80
.;Gain of glycosylation at Y246 (P = 0.0331);
MVP
0.39
MPC
1.2
ClinPred
0.96
D
GERP RS
-6.3
Varity_R
0.37
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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: rs746058141; hg19: chr3-45763541; API