chrX-135965032-G-A

Position:

• chrX-135965032-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_173470.3(MMGT1):​c.388C>T​(p.Arg130Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000732 in 1,092,974 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 4 hem.)
• Consequence: MMGT1 NM_173470.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

Genes affected

MMGT1 (HGNC:28100): (membrane magnesium transporter 1) Contributes to membrane insertase activity. Involved in protein insertion into ER membrane by stop-transfer membrane-anchor sequence and tail-anchored membrane protein insertion into ER membrane. Is integral component of endoplasmic reticulum membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25651747).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMGT1	NM_173470.3	c.388C>T	p.Arg130Cys	missense_variant	4/4	ENST00000305963.3	NP_775741.1
MMGT1	NM_001330000.2	c.388C>T	p.Arg130Cys	missense_variant	5/5		NP_001316929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMGT1	ENST00000305963.3	c.388C>T	p.Arg130Cys	missense_variant	4/4	1	NM_173470.3	ENSP00000306220.2
MMGT1	ENST00000679621.1	c.388C>T	p.Arg130Cys	missense_variant	5/5			ENSP00000505226.1
MMGT1	ENST00000680510.2	c.*185C>T		3_prime_UTR_variant	3/3			ENSP00000505521.1
MMGT1	ENST00000681201.1	c.*143C>T		3_prime_UTR_variant	3/3			ENSP00000506673.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 182208 Hom.: 0 AF XY: 0.0000150 AC XY: 1 AN XY: 66734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000732 AC: 8 AN: 1092974 Hom.: 0 Cov.: 28 AF XY: 0.0000112 AC XY: 4 AN XY: 358652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000597

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

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

Nov 17, 2022

The c.388C>T (p.R130C) alteration is located in exon 4 (coding exon 4) of the MMGT1 gene. This alteration results from a C to T substitution at nucleotide position 388, causing the arginine (R) at amino acid position 130 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	Benign	0.17
BayesDel_addAF	Benign	-0.0086	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.31
MutPred		0.22		Loss of solvent accessibility (P = 0.0111);
MVP		0.76
MPC		1.1
ClinPred		0.69	D
GERP RS		4.7
Varity_R		0.24
gMVP		0.22

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: rs782214612; hg19: chrX-135047191; COSMIC: COSV60002950;