X-64268808-A-G

Position:

• chrX-64268808-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017677.4(MTMR8):​c.1844T>C​(p.Ile615Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,209,406 control chromosomes in the GnomAD database, including 43 homozygotes. There are 728 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., 348 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (21 hom. 380 hem.)
• Consequence: MTMR8 NM_017677.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.478

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032766163).
• BP6: Variant X-64268808-A-G is Benign according to our data. Variant chrX-64268808-A-G is described in ClinVar as [Benign]. Clinvar id is 3044383.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0122 (1358/111166) while in subpopulation AFR AF= 0.0431 (1317/30523). AF 95% confidence interval is 0.0412. There are 22 homozygotes in gnomad4. There are 348 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR8	NM_017677.4	c.1844T>C	p.Ile615Thr	missense_variant	14/14	ENST00000374852.4	NP_060147.2
LOC112268307	XM_047442705.1	c.170+21002A>G		intron_variant			XP_047298661.1
LOC112268307	XM_047442706.1	c.126-36758A>G		intron_variant			XP_047298662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR8	ENST00000374852.4	c.1844T>C	p.Ile615Thr	missense_variant	14/14	1	NM_017677.4	ENSP00000363985	P1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1357 AN: 111113 Hom.: 22 Cov.: 23 AF XY: 0.0104 AC XY: 348 AN XY: 33327

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000382

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000566

Gnomad OTH AF: 0.00666

GnomAD3 exomes AF: 0.00335 AC: 615 AN: 183354 Hom.: 10 AF XY: 0.00206 AC XY: 140 AN XY: 67800

Gnomad AFR exome AF: 0.0441

Gnomad AMR exome AF: 0.000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00127 AC: 1395 AN: 1098240 Hom.: 21 Cov.: 31 AF XY: 0.00105 AC XY: 380 AN XY: 363594

Gnomad4 AFR exome AF: 0.0449

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000416

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.0122 AC: 1358 AN: 111166 Hom.: 22 Cov.: 23 AF XY: 0.0104 AC XY: 348 AN XY: 33390

Gnomad4 AFR AF: 0.0431

Gnomad4 AMR AF: 0.00267

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000566

Gnomad4 OTH AF: 0.00658

Alfa AF: 0.00119 Hom.: 48

Bravo AF: 0.0133

ESP6500AA AF: 0.0420 AC: 161

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00371 AC: 451

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MTMR8-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.26
DANN	Benign	0.55
DEOGEN2	Benign	0.073	T
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.020	N
REVEL	Uncertain	0.31
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.035
MVP		0.41
MPC		0.0027
ClinPred		0.00049	T
GERP RS		-5.4
Varity_R		0.047
gMVP		0.058

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: rs61746243; hg19: chrX-63488688;