chr7-130499898-C-T

Variant names:

• chr7-130499898-C-T
• rs863223353
• NM_002402.4:c.559C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_002402.4(MEST):​c.559C>T​(p.Pro187Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,418 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MEST NM_002402.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.15
• Publications: 1 publications found

Genes affected

MEST (HGNC:7028): (mesoderm specific transcript) This gene encodes a member of the alpha/beta hydrolase superfamily. It is imprinted, exhibiting preferential expression from the paternal allele in fetal tissues, and isoform-specific imprinting in lymphocytes. The loss of imprinting of this gene has been linked to certain types of cancer and may be due to promotor switching. The encoded protein may play a role in development. Alternatively spliced transcript variants encoding multiple isoforms have been identified for this gene. Pseudogenes of this gene are located on the short arm of chromosomes 3 and 4, and the long arm of chromosomes 6 and 15. [provided by RefSeq, Dec 2011]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-130499898-C-T is Pathogenic according to our data. Variant chr7-130499898-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208394.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002402.4. 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
	MEST	NM_002402.4	MANE Select	c.559C>T	p.Pro187Ser	missense	Exon 7 of 12	NP_002393.2
	MEST	NM_177524.2		c.532C>T	p.Pro178Ser	missense	Exon 7 of 12	NP_803490.1	A4D1L9
	MEST	NM_177525.2		c.532C>T	p.Pro178Ser	missense	Exon 7 of 12	NP_803491.1	Q5EB52-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEST	ENST00000223215.10	TSL:1 MANE Select	c.559C>T	p.Pro187Ser	missense	Exon 7 of 12	ENSP00000223215.4	Q5EB52-1
	MEST	ENST00000341441.9	TSL:1	c.532C>T	p.Pro178Ser	missense	Exon 7 of 12	ENSP00000342749.4	Q5EB52-2
	MEST	ENST00000416162.7	TSL:1	c.532C>T	p.Pro178Ser	missense	Exon 7 of 11	ENSP00000408933.2	Q5EB52-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250428 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460418 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726560

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111316

Other (OTH) AF: 0.0000166 AC: 1 AN: 60318

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Childhood-onset schizophrenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.021	D
Polyphen		0.71	P
Vest4		0.56
MutPred		0.59		Loss of helix (P = 0.079)
MVP		0.77
MPC		1.5
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.42
gMVP		0.86
Mutation Taster		=76/24	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs863223353; hg19: chr7-130139739;