8-11300108-C-G

Position:

• chr8-11300108-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015458.4(MTMR9):​c.377C>G​(p.Ser126Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,476 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (16 hom.)
• Consequence: MTMR9 NM_015458.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.53

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008101612).
• BP6: Variant 8-11300108-C-G is Benign according to our data. Variant chr8-11300108-C-G is described in ClinVar as [Benign]. Clinvar id is 785242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00998 (1519/152250) while in subpopulation AFR AF= 0.034 (1414/41544). AF 95% confidence interval is 0.0326. There are 28 homozygotes in gnomad4. There are 738 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTMR9	NM_015458.4	c.377C>G	p.Ser126Cys	missense_variant	3/10	ENST00000221086.8
MTMR9	XM_047422125.1	c.377C>G	p.Ser126Cys	missense_variant	3/11
MTMR9	XM_017013753.3	c.377C>G	p.Ser126Cys	missense_variant	3/7
MTMR9	XM_011543831.3			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTMR9	ENST00000221086.8	c.377C>G	p.Ser126Cys	missense_variant	3/10	1	NM_015458.4	P1
MTMR9	ENST00000530200.1	c.*123C>G		3_prime_UTR_variant, NMD_transcript_variant	4/11	1
MTMR9	ENST00000526292.1	c.122C>G	p.Ser41Cys	missense_variant	3/10	2
MTMR9	ENST00000528389.1	n.614C>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00988 AC: 1503 AN: 152132 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00263 AC: 662 AN: 251352 Hom.: 10 AF XY: 0.00193 AC XY: 262 AN XY: 135856

Gnomad AFR exome AF: 0.0355

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000986 AC: 1441 AN: 1461226 Hom.: 16 Cov.: 31 AF XY: 0.000872 AC XY: 634 AN XY: 726928

Gnomad4 AFR exome AF: 0.0335

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00998 AC: 1519 AN: 152250 Hom.: 28 Cov.: 32 AF XY: 0.00991 AC XY: 738 AN XY: 74436

Gnomad4 AFR AF: 0.0340

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00368 Hom.: 5

Bravo AF: 0.0118

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0356 AC: 157

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00330 AC: 400

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.42	T;.
Eigen	Benign	-0.059
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.82	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.20	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.077	B;.
Vest4		0.60
MVP		0.88
MPC		0.010
ClinPred		0.013	T
GERP RS		4.4
Varity_R		0.063
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116655282; hg19: chr8-11157617;