8-17300174-A-T

Variant names:

• chr8-17300174-A-T
• NM_004686.5:c.1671T>A

Variant summary

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

The NM_004686.5(MTMR7):​c.1671T>A​(p.Ser557Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MTMR7 NM_004686.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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 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=0.05464968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR7	NM_004686.5	c.1671T>A	p.Ser557Arg	missense_variant	Exon 14 of 14	ENST00000180173.10	NP_004677.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTMR7	ENST00000180173.10	c.1671T>A	p.Ser557Arg	missense_variant	Exon 14 of 14	1	NM_004686.5	ENSP00000180173.4
VPS37A	ENST00000520997.1	n.519A>T		non_coding_transcript_exon_variant	Exon 3 of 3	3
VPS37A	ENST00000519515.1	n.52+2016A>T		intron_variant	Intron 1 of 1	3
VPS37A	ENST00000521162.5	n.*43A>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461770 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1671T>A (p.S557R) alteration is located in exon 14 (coding exon 14) of the MTMR7 gene. This alteration results from a T to A substitution at nucleotide position 1671, causing the serine (S) at amino acid position 557 to be replaced by an arginine (R). 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	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.081
Sift	Benign	0.45	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.23		Gain of MoRF binding (P = 0.0161);
MVP		0.24
MPC		0.020
ClinPred		0.041	T
GERP RS		-0.66
Varity_R		0.089
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-17157683;