1-25458891-A-G

Position:

• chr1-25458891-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018202.6(MACO1):​c.1153A>G​(p.Arg385Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. R385S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MACO1 NM_018202.6 missense, splice_region
• Scores: Splicing: ADA: 0.9896
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71

Genes affected

MACO1 (HGNC:25572): (macoilin 1) Predicted to enable actin filament binding activity and microtubule binding activity. Involved in neuronal signal transduction. Located in rough endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MACO1	NM_018202.6	c.1153A>G	p.Arg385Gly	missense_variant, splice_region_variant	6/11	ENST00000374343.5	NP_060672.2
MACO1	XM_005245931.3	c.1153A>G	p.Arg385Gly	missense_variant, splice_region_variant	6/10		XP_005245988.1
MACO1	NM_001282564.2	c.473+4509A>G		intron_variant			NP_001269493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACO1	ENST00000374343.5	c.1153A>G	p.Arg385Gly	missense_variant, splice_region_variant	6/11	1	NM_018202.6	ENSP00000363463.4
MACO1	ENST00000399766.7	c.473+4509A>G		intron_variant		1		ENSP00000382668.3
MACO1	ENST00000647928.1	n.1153A>G		splice_region_variant, non_coding_transcript_exon_variant	6/11			ENSP00000497738.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.1153A>G (p.R385G) alteration is located in exon 6 (coding exon 6) of the TMEM57 gene. This alteration results from a A to G substitution at nucleotide position 1153, causing the arginine (R) at amino acid position 385 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.98	D
Vest4		0.94
MutPred		0.73		Loss of MoRF binding (P = 0.0059);
MVP		0.54
MPC		2.3
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.64
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.72
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-25785382;