8-124553317-G-A

Position:

• chr8-124553317-G-A

Variant summary

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

The NM_014751.6(MTSS1):​c.1943C>T​(p.Pro648Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: MTSS1 NM_014751.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97

Genes affected

MTSS1 (HGNC:20443): (MTSS I-BAR domain containing 1) Enables actin monomer binding activity; identical protein binding activity; and signaling receptor binding activity. Predicted to be involved in cellular response to fluid shear stress; negative regulation of epithelial cell proliferation; and urogenital system development. Predicted to act upstream of or within several processes, including actin filament polymerization; adherens junction maintenance; and magnesium ion homeostasis. Located in actin cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

NDUFB9 (HGNC:7704): (NADH:ubiquinone oxidoreductase subunit B9) The protein encoded by this gene is a subunit of the mitochondrial oxidative phosphorylation complex I (nicotinamide adenine dinucleotide: ubiquinone oxidoreductase). Complex I is localized to the inner mitochondrial membrane and functions to dehydrogenate nicotinamide adenine dinucleotide and to shuttle electrons to coenzyme Q. Complex I deficiency is the most common defect found in oxidative phosphorylation disorders and results in a range of conditions, including lethal neonatal disease, hypertrophic cardiomyopathy, liver disease, and adult-onset neurodegenerative disorders. Pseudogenes of this gene are found on chromosomes five, seven and eight. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

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=0.27244553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTSS1	NM_014751.6	c.1943C>T	p.Pro648Leu	missense_variant	14/14	ENST00000518547.6	NP_055566.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTSS1	ENST00000518547.6	c.1943C>T	p.Pro648Leu	missense_variant	14/14	1	NM_014751.6	ENSP00000429064	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000882 Hom.: 0

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

Aug 29, 2023

The c.1943C>T (p.P648L) alteration is located in exon 14 (coding exon 14) of the MTSS1 gene. This alteration results from a C to T substitution at nucleotide position 1943, causing the proline (P) at amino acid position 648 to be replaced by a leucine (L). 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	0.075
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T;.;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Benign	0.16
Sift	Benign	0.033	D;D;D;T;D
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		0.48	P;P;.;D;D
Vest4		0.35
MutPred		0.41		.;Loss of loop (P = 0.0288);.;.;.;
MVP		0.44
MPC		0.60
ClinPred		0.92	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.32

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: rs868279277; hg19: chr8-125565558;