chr3-45689493-A-G

Position:

• chr3-45689493-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014016.5(SACM1L):​c.28A>G​(p.Lys10Glu) 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 1,428,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21259284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACM1L	NM_014016.5	c.28A>G	p.Lys10Glu	missense_variant	1/20	ENST00000389061.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACM1L	ENST00000389061.10	c.28A>G	p.Lys10Glu	missense_variant	1/20	1	NM_014016.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000524 AC: 1 AN: 190778 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 102236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000359

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: 0.00000140 AC: 2 AN: 1428382 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000258

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.85	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.18
Sift	Benign	0.34	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.33
MutPred		0.44		Loss of methylation at K10 (P = 0.0033);
MVP		0.61
MPC		0.58
ClinPred		0.39	T
GERP RS		4.3
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Varity_R		0.25
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1378965589; hg19: chr3-45730985;