1-25456807-A-C

Position:

• chr1-25456807-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018202.6(MACO1):​c.628A>C​(p.Lys210Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MACO1 NM_018202.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.89

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13090137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MACO1	NM_018202.6	c.628A>C	p.Lys210Gln	missense_variant	5/11	ENST00000374343.5	NP_060672.2
MACO1	XM_005245931.3	c.628A>C	p.Lys210Gln	missense_variant	5/10		XP_005245988.1
MACO1	NM_001282564.2	c.473+2425A>C		intron_variant			NP_001269493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACO1	ENST00000374343.5	c.628A>C	p.Lys210Gln	missense_variant	5/11	1	NM_018202.6	ENSP00000363463.4
MACO1	ENST00000399766.7	c.473+2425A>C		intron_variant		1		ENSP00000382668.3
MACO1	ENST00000647928.1	n.628A>C		non_coding_transcript_exon_variant	5/11			ENSP00000497738.1
MACO1	ENST00000470035.1	n.167-1584A>C		intron_variant		3

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

Apr 12, 2023

The c.628A>C (p.K210Q) 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 628, causing the lysine (K) at amino acid position 210 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.045
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.77	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.062
Sift	Benign	0.42	T
Sift4G	Benign	0.55	T
Polyphen		0.12	B
Vest4		0.28
MutPred		0.38		Loss of ubiquitination at K210 (P = 0.0011);
MVP		0.093
MPC		0.14
ClinPred		0.80	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-25783298;