8-11300138-A-C

Position:

• chr8-11300138-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015458.4(MTMR9):​c.407A>C​(p.Tyr136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 6.8e-7 (0 hom.)
• Consequence: MTMR9 NM_015458.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.892

Genes affected

MTMR9 (HGNC:14596): (myotubularin related protein 9) This gene encodes a myotubularin-related protein that is atypical to most other members of the myotubularin-related protein family because it has no dual-specificity phosphatase domain. The encoded protein contains a double-helical motif similar to the SET interaction domain, which is thought to have a role in the control of cell proliferation. In mouse, a protein similar to the encoded protein binds with MTMR7, and together they dephosphorylate phosphatidylinositol 3-phosphate and inositol 1,3-bisphosphate. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37396294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR9	NM_015458.4	c.407A>C	p.Tyr136Ser	missense_variant	3/10	ENST00000221086.8	NP_056273.2
MTMR9	XM_047422125.1	c.407A>C	p.Tyr136Ser	missense_variant	3/11		XP_047278081.1
MTMR9	XM_017013753.3	c.407A>C	p.Tyr136Ser	missense_variant	3/7		XP_016869242.1
MTMR9	XM_011543831.3			upstream_gene_variant			XP_011542133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR9	ENST00000221086.8	c.407A>C	p.Tyr136Ser	missense_variant	3/10	1	NM_015458.4	ENSP00000221086	P1
MTMR9	ENST00000530200.1	c.*153A>C		3_prime_UTR_variant, NMD_transcript_variant	4/11	1		ENSP00000436046
MTMR9	ENST00000526292.1	c.152A>C	p.Tyr51Ser	missense_variant	3/10	2		ENSP00000433239
MTMR9	ENST00000528389.1	n.644A>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460760 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726680

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.407A>C (p.Y136S) alteration is located in exon 3 (coding exon 3) of the MTMR9 gene. This alteration results from a A to C substitution at nucleotide position 407, causing the tyrosine (Y) at amino acid position 136 to be replaced by a serine (S). 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	0.090
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	8.1
DANN	Benign	0.90
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.70	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.091	T;D
Sift4G	Benign	0.077	T;T
Polyphen		0.0	B;.
Vest4		0.47
MutPred		0.53		Gain of disorder (P = 0.0071);.;
MVP		0.77
MPC		0.0062
ClinPred		0.13	T
GERP RS		1.5
Varity_R		0.062
gMVP		0.78

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: rs761536304; hg19: chr8-11157647;