15-89750563-G-C

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.669C>G(p.Phe223Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,465,286 control chromosomes in the GnomAD database, including 62,707 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5173 hom., cov: 35)
  • Exomes 𝑓: 0.29 (57534 hom.)
• Consequence: MESP1 NM_018670.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.256

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039317906).
• BP6: Variant 15-89750563-G-C is Benign according to our data. Variant chr15-89750563-G-C is described in ClinVar as [Benign]. Clinvar id is 1629584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP1	NM_018670.4	c.669C>G	p.Phe223Leu	missense_variant	1/2	ENST00000300057.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP1	ENST00000300057.5	c.669C>G	p.Phe223Leu	missense_variant	1/2	1	NM_018670.4	P1
MESP1	ENST00000559894.1	n.115-336C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38878 AN: 152040 Hom.: 5169 Cov.: 35

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.0954

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.276

GnomAD3 exomes AF: 0.218 AC: 17159 AN: 78758 Hom.: 2040 AF XY: 0.226 AC XY: 9845 AN XY: 43562

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.0978

Gnomad SAS exome AF: 0.242

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.292 AC: 383049 AN: 1313138 Hom.: 57534 Cov.: 59 AF XY: 0.293 AC XY: 188451 AN XY: 643374

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.170

Gnomad4 ASJ exome AF: 0.346

Gnomad4 EAS exome AF: 0.0878

Gnomad4 SAS exome AF: 0.291

Gnomad4 FIN exome AF: 0.258

Gnomad4 NFE exome AF: 0.304

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.256 AC: 38909 AN: 152148 Hom.: 5173 Cov.: 35 AF XY: 0.253 AC XY: 18792 AN XY: 74360

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.0957

Gnomad4 SAS AF: 0.291

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.301

Gnomad4 OTH AF: 0.276

Alfa AF: 0.275 Hom.: 1174

Bravo AF: 0.250

TwinsUK AF: 0.298 AC: 1104

ALSPAC AF: 0.291 AC: 1121

ESP6500AA AF: 0.143 AC: 435

ESP6500EA AF: 0.220 AC: 1383

ExAC AF: 0.189 AC: 19070

Asia WGS AF: 0.179 AC: 621 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MESP1-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	6.6
Dann	Benign	0.84
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.062
Sift	Benign	0.23	T
Sift4G	Benign	0.65	T
Polyphen		0.0010	B
Vest4		0.088
MutPred		0.32		Loss of loop (P = 0.0203);
MPC		0.53
ClinPred		0.0025	T
GERP RS		0.42
Varity_R		0.054
gMVP		0.093

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: rs2305440; hg19: chr15-90293794;