Variant 3-45709543-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014016.5(SACM1L):c.379A>C(p.Asn127His) variant causes a missense change. The variant allele was found at a frequency of 0.0000545 in 1,613,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SACM1L
NM_014016.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.69

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]

SACM1L links:

SACM1L (HGNC:):

SACM1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043491274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACM1L	NM_014016.5 linkuse as main transcript	c.379A>C	p.Asn127His	missense_variant	5/20	ENST00000389061.10	NP_054735.3	Q9NTJ5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACM1L	ENST00000389061.10 linkuse as main transcript	c.379A>C	p.Asn127His	missense_variant	5/20	1	NM_014016.5	ENSP00000373713.4		Q9NTJ5-1

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.0000797

AC:

AN:

250978

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.0000291

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461450

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.0000448

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000315

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000378

Hom.:

Bravo

AF:

0.000366

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

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 submitter

clinical testing

Ambry Genetics

Jun 07, 2024

The c.379A>C (p.N127H) alteration is located in exon 5 (coding exon 5) of the SACM1L gene. This alteration results from a A to C substitution at nucleotide position 379, causing the asparagine (N) at amino acid position 127 to be replaced by a histidine (H). 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

0.059

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

.;T;.

Eigen

Benign

0.090

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

T;T;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.1

.;L;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.087

T;T;D

Sift4G

Benign

0.10

T;T;D

Polyphen

0.0010

.;B;.

Vest4

0.25

MVP

0.20

MPC

0.43

ClinPred

0.055

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.27

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over