8-17300096-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004686.5(MTMR7):c.1749T>G(p.Ser583Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,614,040 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (13 hom.)
• Consequence: MTMR7 NM_004686.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0940

Genes affected

MTMR7 (HGNC:7454): (myotubularin related protein 7) This gene encodes a member of the myotubularin family of tyrosine/dual-specificity phosphatases. The encoded protein is characterized by four distinct domains that are conserved among all members of the myotubularin family: the glucosyltransferase, Rab-like GTPase activator and myotubularins domain, the Rac-induced recruitment domain, the protein tyrosine phosphatases and dual-specificity phosphatases domain and the suppressor of variegation 3-9, enhancer-of-zeste, and trithorax interaction domain. This protein dephosphorylates the target substrates phosphatidylinositol 3-phosphate and inositol 1,3-bisphosphate. A pseudogene of this gene is found on chromosome 5. [provided by RefSeq, Mar 2009]

VPS37A (HGNC:24928): (VPS37A subunit of ESCRT-I) This gene belongs to the VPS37 family, and encodes a component of the ESCRT-I (endosomal sorting complex required for transport I) protein complex, required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. Expression of this gene is downregulated in hepatocellular carcinoma, and mutations in this gene are associated with autosomal recessive spastic paraplegia-53. A related pseudogene has been identified on chromosome 5. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057281256).
• BP6: Variant 8-17300096-A-C is Benign according to our data. Variant chr8-17300096-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3044627.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTMR7	NM_004686.5	c.1749T>G	p.Ser583Arg	missense_variant	14/14	ENST00000180173.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTMR7	ENST00000180173.10	c.1749T>G	p.Ser583Arg	missense_variant	14/14	1	NM_004686.5	P1
VPS37A	ENST00000520997.1	n.441A>C		non_coding_transcript_exon_variant	3/3	3
VPS37A	ENST00000521162.5	n.783A>C		non_coding_transcript_exon_variant	3/3	2
VPS37A	ENST00000519515.1	n.52+1938A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 349 AN: 152052 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00218 AC: 548 AN: 251082 Hom.: 3 AF XY: 0.00228 AC XY: 310 AN XY: 135682

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00392

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00391 AC: 5715 AN: 1461870 Hom.: 13 Cov.: 31 AF XY: 0.00390 AC XY: 2839 AN XY: 727240

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00471

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.00229 AC: 349 AN: 152170 Hom.: 4 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74394

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00410

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00358 Hom.: 6

Bravo AF: 0.00225

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00224 AC: 272

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00326

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MTMR7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2022

This variant is classified as likely 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	0.24
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	7.5
Dann	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.41
Sift	Benign	0.28	T
Sift4G	Benign	0.55	T
Polyphen		0.20	B
Vest4		0.25
MutPred		0.21		Loss of glycosylation at S583 (P = 0.0105);
MVP		0.71
MPC		0.027
ClinPred		0.0055	T
GERP RS		-2.6
Varity_R		0.11
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs145244130; hg19: chr8-17157605;