Genetic Variant MSC:p.Ser7Arg (chr8-71844158-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005098.4(MSC):c.21T>A(p.Ser7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,602 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

MSC
NM_005098.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.603

Variant links:

Genes affected

MSC (HGNC:7321): (musculin) The protein encoded by this gene is a transcriptional repressor capable of binding an E-box element either as a homodimer or as a heterodimer with E2A in vitro. The encoded protein also forms heterodimers with E2A proteins in vivo. This protein is capable of inhibiting the transactivation capability of E47, an E2A protein, in mammalian cells. This gene is a downstream target of the B-cell receptor signal transduction pathway. [provided by RefSeq, Jul 2008]

MSC links:

MSC-AS1 (HGNC:48724): (MSC antisense RNA 1)

MSC-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSC	NM_005098.4 link	c.21T>A	p.Ser7Arg	missense_variant	Exon 1 of 2	ENST00000325509.5	NP_005089.2	O60682
MSC-AS1	NR_033651.1 link	n.43A>T		non_coding_transcript_exon_variant	Exon 1 of 3
MSC-AS1	NR_033652.1 link	n.583-71A>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSC	ENST00000325509.5 link	c.21T>A	p.Ser7Arg	missense_variant	Exon 1 of 2	1	NM_005098.4	ENSP00000321445.4		O60682

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1395602

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686686

show subpopulations

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:

0.0000131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.21T>A (p.S7R) alteration is located in exon 1 (coding exon 1) of the MSC gene. This alteration results from a T to A substitution at nucleotide position 21, causing the serine (S) at amino acid position 7 to be replaced by an arginine (R). 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

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.52

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

1.9

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.23

MutPred

0.28

Loss of phosphorylation at S7 (P = 0.0061);

MVP

0.86

MPC

2.0

ClinPred

0.98

GERP RS

1.7

Varity_R

0.53

gMVP

0.56

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over