1-25456812-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_018202.6(MACO1):c.633A>C(p.Gln211His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000702 in 1,610,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

MACO1
NM_018202.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.942

Variant links:

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]

MACO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, MACO1

BP4

Computational evidence support a benign effect (MetaRNN=0.09344125).

BS2

High AC in GnomAd at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MACO1	NM_018202.6 linkuse as main transcript	c.633A>C	p.Gln211His	missense_variant	5/11	ENST00000374343.5
MACO1	XM_005245931.3 linkuse as main transcript	c.633A>C	p.Gln211His	missense_variant	5/10
MACO1	NM_001282564.2 linkuse as main transcript	c.473+2430A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACO1	ENST00000374343.5 linkuse as main transcript	c.633A>C	p.Gln211His	missense_variant	5/11	1	NM_018202.6	P1	Q8N5G2-1
MACO1	ENST00000399766.7 linkuse as main transcript	c.473+2430A>C		intron_variant		1			Q8N5G2-3
MACO1	ENST00000647928.1 linkuse as main transcript	c.633A>C	p.Gln211His	missense_variant, NMD_transcript_variant	5/11
MACO1	ENST00000470035.1 linkuse as main transcript	n.167-1579A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000699

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000811

AC:

AN:

246682

Hom.:

AF XY:

0.0000823

AC XY:

AN XY:

133648

show subpopulations

Gnomad AFR exome

AF:

0.000622

Gnomad AMR exome

AF:

0.0000308

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000622

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.0000535

AC:

AN:

1458020

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

725522

show subpopulations

Gnomad4 AFR exome

AF:

0.000908

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.000233

GnomAD4 genome

AF:

0.000230

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000699

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000952

Hom.:

Bravo

AF:

0.000287

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.633A>C (p.Q211H) alteration is located in exon 5 (coding exon 5) of the TMEM57 gene. This alteration results from a A to C substitution at nucleotide position 633, causing the glutamine (Q) at amino acid position 211 to be replaced by a histidine (H). 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

Benign

0.21

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.19

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.036

Eigen

Benign

0.059

Eigen_PC

Benign

0.083

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0062

MetaRNN

Benign

0.093

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.2

REVEL

Benign

0.13

Sift

Uncertain

0.028

Sift4G

Benign

0.12

Polyphen

0.88

Vest4

0.49

MutPred

0.55

Loss of methylation at K213 (P = 0.1487);

MVP

0.12

MPC

0.39

ClinPred

0.049

GERP RS

2.4

Varity_R

0.14

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over