rs28368490

chr15-89751050-A-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.182T>G(p.Leu61Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,317,352 control chromosomes in the GnomAD database, including 41,669 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5827 hom., cov: 34)
  • Exomes 𝑓: 0.24 (35842 hom.)
• Consequence: MESP1 NM_018670.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.79

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=0.005183816).
• BP6: Variant 15-89751050-A-C is Benign according to our data. Variant chr15-89751050-A-C is described in ClinVar as [Benign]. Clinvar id is 1548747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89751050-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP1	NM_018670.4	c.182T>G	p.Leu61Arg	missense_variant	1/2	ENST00000300057.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP1	ENST00000300057.5	c.182T>G	p.Leu61Arg	missense_variant	1/2	1	NM_018670.4	P1
MESP1	ENST00000559894.1	n.88T>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40639 AN: 151196 Hom.: 5821 Cov.: 34

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.221

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.250

GnomAD3 exomes AF: 0.0267 AC: 218 AN: 8172 Hom.: 10 AF XY: 0.0268 AC XY: 124 AN XY: 4620

Gnomad AFR exome AF: 0.0907

Gnomad AMR exome AF: 0.00690

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00643

Gnomad SAS exome AF: 0.0271

Gnomad FIN exome AF: 0.00645

Gnomad NFE exome AF: 0.0286

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.242 AC: 281777 AN: 1166050 Hom.: 35842 Cov.: 56 AF XY: 0.239 AC XY: 134631 AN XY: 562464

Gnomad4 AFR exome AF: 0.365

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.269 AC: 40667 AN: 151302 Hom.: 5827 Cov.: 34 AF XY: 0.262 AC XY: 19362 AN XY: 73958

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.287

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.247

Alfa AF: 0.257 Hom.: 629

Bravo AF: 0.273

ExAC AF: 0.0179 AC: 1401

Asia WGS AF: 0.211 AC: 731 AN: 3452

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	Benign	0.042
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.37
Dann	Benign	0.24
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.097
Sift	Benign	0.48	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.65
ClinPred		0.0040	T
GERP RS		-1.6
Varity_R		0.080
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs28368490; hg19: chr15-90294281; COSMIC: COSV55588418; COSMIC: COSV55588418;