rs2305441

Positions:

• chr15-89750545-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018670.4(MESP1):​c.687T>G​(p.Pro229=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,481,144 control chromosomes in the GnomAD database, including 296,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33519 hom., cov: 35)
  • Exomes 𝑓: 0.62 (262530 hom.)
• Consequence: MESP1 NM_018670.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.22

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 15-89750545-A-C is Benign according to our data. Variant chr15-89750545-A-C is described in ClinVar as [Benign]. Clinvar id is 1601156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP1	NM_018670.4	c.687T>G	p.Pro229=	synonymous_variant	1/2	ENST00000300057.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP1	ENST00000300057.5	c.687T>G	p.Pro229=	synonymous_variant	1/2	1	NM_018670.4	P1
MESP1	ENST00000559894.1	n.115-318T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98630 AN: 151894 Hom.: 33486 Cov.: 35

Gnomad AFR AF: 0.819

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.647

GnomAD3 exomes AF: 0.549 AC: 55024 AN: 100312 Hom.: 16041 AF XY: 0.562 AC XY: 31528 AN XY: 56062

Gnomad AFR exome AF: 0.801

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.679

Gnomad EAS exome AF: 0.275

Gnomad SAS exome AF: 0.626

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.577

GnomAD4 exome AF: 0.623 AC: 828268 AN: 1329138 Hom.: 262530 Cov.: 56 AF XY: 0.624 AC XY: 407468 AN XY: 652522

Gnomad4 AFR exome AF: 0.832

Gnomad4 AMR exome AF: 0.403

Gnomad4 ASJ exome AF: 0.709

Gnomad4 EAS exome AF: 0.278

Gnomad4 SAS exome AF: 0.656

Gnomad4 FIN exome AF: 0.491

Gnomad4 NFE exome AF: 0.634

Gnomad4 OTH exome AF: 0.631

GnomAD4 genome AF: 0.649 AC: 98713 AN: 152006 Hom.: 33519 Cov.: 35 AF XY: 0.635 AC XY: 47177 AN XY: 74266

Gnomad4 AFR AF: 0.820

Gnomad4 AMR AF: 0.511

Gnomad4 ASJ AF: 0.719

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.636

Gnomad4 FIN AF: 0.470

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.644

Alfa AF: 0.632 Hom.: 6729

Bravo AF: 0.659

Asia WGS AF: 0.486 AC: 1691 AN: 3470

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

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
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.43

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: rs2305441; hg19: chr15-90293776;