8-71843938-C-G

Variant names:

• chr8-71843938-C-G
• rs747587360
• NM_005098.4:c.241G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005098.4(MSC):​c.241G>C​(p.Gly81Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G81S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MSC NM_005098.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.590
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12404922).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005098.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSC	NM_005098.4	MANE Select	c.241G>C	p.Gly81Arg	missense	Exon 1 of 2	NP_005089.2	O60682
	MSC-AS1	NR_033652.1		n.582+234C>G		intron	N/A
	MSC-AS1	NR_033651.1		n.-178C>G		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSC	ENST00000325509.5	TSL:1 MANE Select	c.241G>C	p.Gly81Arg	missense	Exon 1 of 2	ENSP00000321445.4	O60682
	MSC	ENST00000912144.1		c.15+226G>C		intron	N/A	ENSP00000582203.1
	MSC-AS1	ENST00000521467.5	TSL:3	n.49+15723C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410988 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698032

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32080

American (AMR) AF: 0.00 AC: 0 AN: 37778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25212

East Asian (EAS) AF: 0.00 AC: 0 AN: 36466

South Asian (SAS) AF: 0.00 AC: 0 AN: 81442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5398

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088424

Other (OTH) AF: 0.00 AC: 0 AN: 58488

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.073	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.2	L
PhyloP100		-0.59
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.28	N
REVEL	Benign	0.29
Sift	Benign	0.13	T
Sift4G	Benign	0.43	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.41		Gain of methylation at G81 (P = 0.0023)
MVP		0.38
MPC		1.1
ClinPred		0.12	T
GERP RS		0.29
PromoterAI		-0.11	Neutral
Varity_R		0.081
gMVP		0.28
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs747587360; hg19: chr8-72756173;