2-17816993-G-T

Variant names:

• chr2-17816993-G-T
• rs372248857
• NM_001105569.3:c.475G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001105569.3(MSGN1):​c.475G>T​(p.Gly159Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G159S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSGN1 NM_001105569.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81
• Publications: 0 publications found

Genes affected

MSGN1 (HGNC:14907): (mesogenin 1) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in mesoderm formation and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within segment specification and somitogenesis. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MSGN1 Gene-Disease associations (from GenCC):

• skeletal dysplasia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000297720 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105569.3. 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
	MSGN1	NM_001105569.3	MANE Select	c.475G>T	p.Gly159Cys	missense	Exon 1 of 1	NP_001099039.1	A6NI15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSGN1	ENST00000281047.4	TSL:6 MANE Select	c.475G>T	p.Gly159Cys	missense	Exon 1 of 1	ENSP00000281047.3	A6NI15
	ENSG00000297720	ENST00000750479.1		n.454-12039C>A		intron	N/A
	ENSG00000297720	ENST00000750480.1		n.416-8260C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 73

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.50		Loss of disorder (P = 0.081)
MVP		0.85
MPC		0.65
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.82
gMVP		0.84
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs372248857; hg19: chr2-17998260;