rs6496598

Positions:

• chr15-89751075-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018670.4(MESP1):​c.157G>C​(p.Ala53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,315,716 control chromosomes in the GnomAD database, including 58,559 homozygotes. 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.33 (9195 hom., cov: 34)
  • Exomes 𝑓: 0.28 (49364 hom.)
• Consequence: MESP1 NM_018670.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.03

Genes affected

MESP1 (HGNC:29658): (mesoderm posterior bHLH transcription factor 1) Enables DNA-binding transcription factor activity and transcription cis-regulatory region binding activity. Involved in several processes, including endothelial cell differentiation; heart development; and positive regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MESP1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1452904E-6).
• BP6: Variant 15-89751075-C-G is Benign according to our data. Variant chr15-89751075-C-G is described in ClinVar as [Benign]. Clinvar id is 1598905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MESP1	NM_018670.4	c.157G>C	p.Ala53Pro	missense_variant	1/2	ENST00000300057.5	NP_061140.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MESP1	ENST00000300057.5	c.157G>C	p.Ala53Pro	missense_variant	1/2	1	NM_018670.4	ENSP00000300057.4
MESP1	ENST00000559894.1	n.63G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49526 AN: 151600 Hom.: 9197 Cov.: 34

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.0896

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.321

GnomAD3 exomes AF: 0.338 AC: 6783 AN: 20060 Hom.: 1440 AF XY: 0.345 AC XY: 3939 AN XY: 11412

Gnomad AFR exome AF: 0.761

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.110

Gnomad SAS exome AF: 0.429

Gnomad FIN exome AF: 0.324

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.281 AC: 327564 AN: 1164012 Hom.: 49364 Cov.: 52 AF XY: 0.284 AC XY: 159051 AN XY: 559250

Gnomad4 AFR exome AF: 0.544

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.341

Gnomad4 EAS exome AF: 0.0792

Gnomad4 SAS exome AF: 0.384

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.277

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.327 AC: 49550 AN: 151704 Hom.: 9195 Cov.: 34 AF XY: 0.320 AC XY: 23724 AN XY: 74158

Gnomad4 AFR AF: 0.511

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.320

Gnomad4 EAS AF: 0.0897

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.322

Alfa AF: 0.541 Hom.: 2777

Bravo AF: 0.601

ExAC AF: 0.289 AC: 23815

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

MESP1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.7
DANN	Benign	0.60
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.58
ClinPred		0.0053	T
GERP RS		2.5
Varity_R		0.065
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs6496598; hg19: chr15-90294306; COSMIC: COSV55588502; COSMIC: COSV55588502;