X-64268649-C-T

Position:

• chrX-64268649-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017677.4(MTMR8):​c.2003G>A​(p.Gly668Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000819 in 1,098,242 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 1 hem.)
• Consequence: MTMR8 NM_017677.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.802

Genes affected

MTMR8 (HGNC:16825): (myotubularin related protein 8) This gene encodes a member of the myotubularin-related family and is part of the MTMR6 subgroup. Family members are dual-specificity phosphatases and the encoded protein contains a phosphoinositide-binding domain (PID) and a SET-interacting domain (SID). Defects in other family members have been found in myotubular myopathic diseases. [provided by RefSeq, Mar 2010]

LOC112268307 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05814737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR8	NM_017677.4	c.2003G>A	p.Gly668Glu	missense_variant	14/14	ENST00000374852.4	NP_060147.2
LOC112268307	XM_047442705.1	c.170+20843C>T		intron_variant			XP_047298661.1
LOC112268307	XM_047442706.1	c.126-36917C>T		intron_variant			XP_047298662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR8	ENST00000374852.4	c.2003G>A	p.Gly668Glu	missense_variant	14/14	1	NM_017677.4	ENSP00000363985	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000819 AC: 9 AN: 1098242 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363596

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.00000831

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

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 06, 2024

The c.2003G>A (p.G668E) alteration is located in exon 14 (coding exon 14) of the MTMR8 gene. This alteration results from a G to A substitution at nucleotide position 2003, causing the glycine (G) at amino acid position 668 to be replaced by a glutamic acid (E). 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	0.075
BayesDel_addAF	Benign	0.0039	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.12
DANN	Benign	0.70
DEOGEN2	Benign	0.065	T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.29
Sift	Benign	0.34	T
Sift4G	Benign	0.090	T
Polyphen		0.0030	B
Vest4		0.040
MutPred		0.46		Loss of glycosylation at S667 (P = 0.0666);
MVP		0.44
MPC		0.0026
ClinPred		0.029	T
GERP RS		-2.6
Varity_R		0.069
gMVP		0.19

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: rs867210552; hg19: chrX-63488529;