19-48713994-T-C

Variant summary

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

The NM_001130915.2(MAMSTR):c.775A>G(p.Thr259Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,294 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAMSTR NM_001130915.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.268

Genes affected

MAMSTR (HGNC:26689): (MEF2 activating motif and SAP domain containing transcriptional regulator) Predicted to enable transcription coregulator activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within positive regulation of myotube differentiation and positive regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.04306394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAMSTR	NM_001130915.2	c.775A>G	p.Thr259Ala	missense_variant	8/10	ENST00000318083.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAMSTR	ENST00000318083.11	c.775A>G	p.Thr259Ala	missense_variant	8/10	2	NM_001130915.2	P2
MAMSTR	ENST00000594582.1	c.271A>G	p.Thr91Ala	missense_variant	5/7	1
MAMSTR	ENST00000356751.8	c.466A>G	p.Thr156Ala	missense_variant	6/8	2		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459294 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 725816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

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.: 33

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

Jun 22, 2021

The c.775A>G (p.T259A) alteration is located in exon 8 (coding exon 7) of the MAMSTR gene. This alteration results from a A to G substitution at nucleotide position 775, causing the threonine (T) at amino acid position 259 to be replaced by an alanine (A). 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	0.081
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	5.9
Dann	Benign	0.61
DEOGEN2	Benign	0.017	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.37	T;T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.52	N;N;.
REVEL	Benign	0.023
Sift	Benign	0.69	T;T;.
Sift4G	Benign	0.85	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.037
MutPred		0.14		Loss of phosphorylation at T259 (P = 0.006);.;.;
MVP		0.095
MPC		0.39
ClinPred		0.073	T
GERP RS		-0.83
Varity_R		0.036
gMVP		0.12

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: rs1431761881; hg19: chr19-49217251;