3-45719518-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014016.5(SACM1L):​c.596G>T​(p.Cys199Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,022 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C199S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SACM1L NM_014016.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.95
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>T	p.Cys199Phe	missense	Exon 8 of 20	NP_054735.3
	SACM1L	NM_001319071.2		c.596G>T	p.Cys199Phe	missense	Exon 8 of 20	NP_001306000.1	A0A5F9ZHN7
	SACM1L	NM_001319072.2		c.413G>T	p.Cys138Phe	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>T	p.Cys199Phe	missense	Exon 8 of 20	ENSP00000373713.4	Q9NTJ5-1
	SACM1L	ENST00000455997.5	TSL:1	n.287G>T		non_coding_transcript_exon	Exon 8 of 20	ENSP00000389975.1	F8WDN7
	SACM1L	ENST00000672858.2		c.596G>T	p.Cys199Phe	missense	Exon 8 of 20	ENSP00000500542.2	A0A5F9ZHN7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452022 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722866

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.00 AC: 0 AN: 44058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 85464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104696

Other (OTH) AF: 0.00 AC: 0 AN: 60024

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.013	D
Sift4G	Benign	0.082	T
Polyphen		0.20	B
Vest4		0.73
MutPred		0.52		Loss of sheet (P = 0.1158)
MVP		0.38
MPC		0.75
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.70
gMVP		0.81
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs374692887; hg19: chr3-45761010;