chr8-17653275-T-C

Variant names:

• chr8-17653275-T-C
• rs201400993
• NM_001363059.2:c.3295A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001363059.2(MTUS1):​c.3295A>G​(p.Ile1099Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,552,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MTUS1 NM_001363059.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 1 publications found

Genes affected

MTUS1 (HGNC:29789): (microtubule associated scaffold protein 1) This gene encodes a protein which contains a C-terminal domain able to interact with the angiotension II (AT2) receptor and a large coiled-coil region allowing dimerization. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. One of the transcript variants has been shown to encode a mitochondrial protein that acts as a tumor suppressor and partcipates in AT2 signaling pathways. Other variants may encode nuclear or transmembrane proteins but it has not been determined whether they also participate in AT2 signaling pathways. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008882791).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTUS1	NM_001363059.2	c.3295A>G	p.Ile1099Val	missense_variant	Exon 12 of 15	ENST00000693296.1	NP_001349988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTUS1	ENST00000693296.1	c.3295A>G	p.Ile1099Val	missense_variant	Exon 12 of 15		NM_001363059.2	ENSP00000509719.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000125 AC: 23 AN: 183834 AF XY: 0.000120

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000221

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000469

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.0000357 AC: 50 AN: 1400110 Hom.: 0 Cov.: 27 AF XY: 0.0000317 AC XY: 22 AN XY: 694538

African (AFR) AF: 0.000456 AC: 14 AN: 30698

American (AMR) AF: 0.000382 AC: 11 AN: 28830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24474

East Asian (EAS) AF: 0.00 AC: 0 AN: 38904

South Asian (SAS) AF: 0.00 AC: 0 AN: 77524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1083876

Other (OTH) AF: 0.000207 AC: 12 AN: 58002

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74496

African (AFR) AF: 0.000794 AC: 33 AN: 41572

American (AMR) AF: 0.000981 AC: 15 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000688

ESP6500AA AF: 0.00193 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000116 AC: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3295A>G (p.I1099V) alteration is located in exon 12 (coding exon 11) of the MTUS1 gene. This alteration results from a A to G substitution at nucleotide position 3295, causing the isoleucine (I) at amino acid position 1099 to be replaced by a valine (V). 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	0.17
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.040	.;.;.;.;T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T;T;T;T;.;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0089	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.78	.;.;.;.;N;.;.
PhyloP100		3.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N;.
REVEL	Benign	0.076
Sift	Benign	0.61	T;T;T;T;T;T;.
Sift4G	Benign	0.28	T;T;T;T;T;T;T
Polyphen		0.29, 0.0040, 0.18	.;B;B;B;B;B;.
Vest4		0.37
MVP		0.19
ClinPred		0.021	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.24
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs201400993; hg19: chr8-17510784;