NM_014016.5:c.17A>C

Variant names:

• chr3-45689482-A-C
• rs750652021
• NM_014016.5:c.17A>C

Variant summary

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

The NM_014016.5(SACM1L):​c.17A>C​(p.Tyr6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,286 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. Y6F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SACM1L NM_014016.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98
• 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.17A>C	p.Tyr6Ser	missense	Exon 1 of 20	NP_054735.3
	SACM1L	NM_001319071.2		c.17A>C	p.Tyr6Ser	missense	Exon 1 of 20	NP_001306000.1	A0A5F9ZHN7
	SACM1L	NM_001319072.2		c.-39A>C		5_prime_UTR	Exon 1 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.17A>C	p.Tyr6Ser	missense	Exon 1 of 20	ENSP00000373713.4	Q9NTJ5-1
	SACM1L	ENST00000455997.5	TSL:1	n.-1183A>C		non_coding_transcript_exon	Exon 1 of 20	ENSP00000389975.1	F8WDN7
	SACM1L	ENST00000455997.5	TSL:1	n.-1183A>C		5_prime_UTR	Exon 1 of 20	ENSP00000389975.1	F8WDN7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000527 AC: 1 AN: 189862 AF XY: 0.00000984

Gnomad AFR exome AF: 0.00

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 AF: 7.01e-7 AC: 1 AN: 1427286 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 706338

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32990

American (AMR) AF: 0.00 AC: 0 AN: 38496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25438

East Asian (EAS) AF: 0.00 AC: 0 AN: 38236

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095790

Other (OTH) AF: 0.00 AC: 0 AN: 59120

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.039
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.21
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.15	B
Vest4		0.59
MutPred		0.61		Gain of disorder (P = 0.0126)
MVP		0.49
MPC		0.75
ClinPred		0.97	D
GERP RS		4.3
PromoterAI		-0.17	Neutral
Varity_R		0.39
gMVP		0.86
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs750652021; hg19: chr3-45730974;