Genetic Variant NM_014016.5:c.11C>T (chr3-45689476-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014016.5(SACM1L):c.11C>T(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,425,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SACM1L
NM_014016.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.940

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040912926).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014016.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SACM1L	NM_014016.5	MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 20	NP_054735.3
SACM1L	NM_001319071.2		c.11C>T	p.Ala4Val	missense	Exon 1 of 20	NP_001306000.1	A0A5F9ZHN7
SACM1L	NM_001319072.2		c.-45C>T		5_prime_UTR	Exon 1 of 19	NP_001306001.1	Q9NTJ5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SACM1L	ENST00000389061.10	TSL:1 MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 20	ENSP00000373713.4	Q9NTJ5-1
SACM1L	ENST00000455997.5	TSL:1	n.-1189C>T		non_coding_transcript_exon	Exon 1 of 20	ENSP00000389975.1	F8WDN7
SACM1L	ENST00000455997.5	TSL:1	n.-1189C>T		5_prime_UTR	Exon 1 of 20	ENSP00000389975.1	F8WDN7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1425752

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

705464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32936

American (AMR)

AF:

0.00

AC:

AN:

38240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25420

East Asian (EAS)

AF:

0.00

AC:

AN:

38132

South Asian (SAS)

AF:

0.00

AC:

AN:

81432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5488

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1095036

Other (OTH)

AF:

0.00

AC:

AN:

59074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.013

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.42

M_CAP

Benign

0.035

MetaRNN

Benign

0.041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.94

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.55

REVEL

Benign

0.028

Sift

Benign

0.54

Sift4G

Benign

0.36

Polyphen

0.071

Vest4

0.042

MutPred

0.31

Gain of glycosylation at Y6 (P = 0.0257)

MVP

0.13

MPC

0.41

ClinPred

0.079

GERP RS

2.6

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.4

Varity_R

0.037

gMVP

0.43

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over