3-45719518-G-C

Variant names:

• chr3-45719518-G-C
• rs374692887
• NM_014016.5:c.596G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014016.5(SACM1L):​c.596G>C​(p.Cys199Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 152,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C199Y) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000033 (0 hom., cov: 32)
• Consequence: SACM1L NM_014016.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29163715).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACM1L	NM_014016.5	MANE Select	c.596G>C	p.Cys199Ser	missense	Exon 8 of 20	NP_054735.3
	SACM1L	NM_001319071.2		c.596G>C	p.Cys199Ser	missense	Exon 8 of 20	NP_001306000.1	A0A5F9ZHN7
	SACM1L	NM_001319072.2		c.413G>C	p.Cys138Ser	missense	Exon 7 of 19	NP_001306001.1	Q9NTJ5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACM1L	ENST00000389061.10	TSL:1 MANE Select	c.596G>C	p.Cys199Ser	missense	Exon 8 of 20	ENSP00000373713.4	Q9NTJ5-1
	SACM1L	ENST00000455997.5	TSL:1	n.287G>C		non_coding_transcript_exon	Exon 8 of 20	ENSP00000389975.1	F8WDN7
	SACM1L	ENST00000672858.2		c.596G>C	p.Cys199Ser	missense	Exon 8 of 20	ENSP00000500542.2	A0A5F9ZHN7

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249014 AF XY: 0.0000149

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74314

African (AFR) AF: 0.000121 AC: 5 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.28
Sift	Benign	0.035	D
Sift4G	Benign	0.12	T
Polyphen		0.082	B
Vest4		0.41
MutPred		0.72		Gain of disorder (P = 0.0029)
MVP		0.16
MPC		0.53
ClinPred		0.66	D
GERP RS		5.7
Varity_R		0.49
gMVP		0.75
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs374692887; hg19: chr3-45761010;