chrX-64348781-C-T

Variant names:

• chrX-64348781-C-T
• rs201816063
• NM_017677.4:c.611G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_017677.4(MTMR8):​c.611G>A​(p.Arg204His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000091 in 1,208,401 control chromosomes in the GnomAD database, including 1 homozygotes. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.000090 (1 hom. 28 hem.)
• Consequence: MTMR8 NM_017677.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• Publications: 1 publications found

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]

ENSG00000287370 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23512855).
• BS2: High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR8	NM_017677.4	c.611G>A	p.Arg204His	missense_variant	Exon 6 of 14	ENST00000374852.4	NP_060147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTMR8	ENST00000374852.4	c.611G>A	p.Arg204His	missense_variant	Exon 6 of 14	1	NM_017677.4	ENSP00000363985.3

Frequencies

GnomAD3 genomes AF: 0.0000984 AC: 11 AN: 111819 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000948

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00198

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000988 AC: 18 AN: 182252 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000580

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.000446

GnomAD4 exome AF: 0.0000903 AC: 99 AN: 1096529 Hom.: 1 Cov.: 30 AF XY: 0.0000773 AC XY: 28 AN XY: 362373

African (AFR) AF: 0.000114 AC: 3 AN: 26338

American (AMR) AF: 0.000114 AC: 4 AN: 35073

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19324

East Asian (EAS) AF: 0.00136 AC: 41 AN: 30161

South Asian (SAS) AF: 0.000111 AC: 6 AN: 54005

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40426

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4124

European-Non Finnish (NFE) AF: 0.0000404 AC: 34 AN: 841078

Other (OTH) AF: 0.000217 AC: 10 AN: 46000

GnomAD4 genome AF: 0.0000983 AC: 11 AN: 111872 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 4 AN XY: 34104

African (AFR) AF: 0.00 AC: 0 AN: 30854

American (AMR) AF: 0.0000947 AC: 1 AN: 10560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00199 AC: 7 AN: 3519

South Asian (SAS) AF: 0.00 AC: 0 AN: 2694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6059

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53118

Other (OTH) AF: 0.00 AC: 0 AN: 1527

Alfa AF: 0.0000751 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000548

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.611G>A (p.R204H) alteration is located in exon 6 (coding exon 6) of the MTMR8 gene. This alteration results from a G to A substitution at nucleotide position 611, causing the arginine (R) at amino acid position 204 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	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.24	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		1.5
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.15
MVP		0.76
MPC		0.0083
ClinPred		0.70	D
GERP RS		-0.42
Varity_R		0.79
gMVP		0.89
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201816063; hg19: chrX-63568661; COSMIC: COSV66393506; COSMIC: COSV66393506;