1-25431174-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_018202.6(MACO1):c.76G>T(p.Gly26Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MACO1 NM_018202.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MACO1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACO1	NM_018202.6	c.76G>T	p.Gly26Cys	missense_variant	1/11	ENST00000374343.5
MACO1	NM_001282564.2	c.76G>T	p.Gly26Cys	missense_variant	1/9
MACO1	XM_005245931.3	c.76G>T	p.Gly26Cys	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACO1	ENST00000374343.5	c.76G>T	p.Gly26Cys	missense_variant	1/11	1	NM_018202.6	P1
MACO1	ENST00000399766.7	c.76G>T	p.Gly26Cys	missense_variant	1/9	1
MACO1	ENST00000647928.1	c.76G>T	p.Gly26Cys	missense_variant, NMD_transcript_variant	1/11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441528 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

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.: 32

Bravo AF: 0.00000378

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

Oct 13, 2021

The c.76G>T (p.G26C) alteration is located in exon 1 (coding exon 1) of the TMEM57 gene. This alteration results from a G to T substitution at nucleotide position 76, causing the glycine (G) at amino acid position 26 to be replaced by a cysteine (C). 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	0.71
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Benign	0.97
Eigen	Benign	0.089
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		0.93	P;B
Vest4		0.23
MutPred		0.58		Loss of disorder (P = 0.1197);Loss of disorder (P = 0.1197);
MVP		0.14
MPC		1.4
ClinPred		0.97	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.52
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs2042861391; hg19: chr1-25757665;