15-89750672-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018670.4(MESP1):c.560G>T(p.Arg187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000973 in 1,356,610 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R187R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00055 (2 hom., cov: 34)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: MESP1 NM_018670.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.809

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00868535).
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP1	NM_018670.4	c.560G>T	p.Arg187Leu	missense_variant	1/2	ENST00000300057.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP1	ENST00000300057.5	c.560G>T	p.Arg187Leu	missense_variant	1/2	1	NM_018670.4	P1
MESP1	ENST00000559894.1	n.114+352G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152144 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000185 AC: 1 AN: 5402 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3052

Gnomad AFR exome AF: 0.00362

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000399 AC: 48 AN: 1204358 Hom.: 0 Cov.: 66 AF XY: 0.0000292 AC XY: 17 AN XY: 582302

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.000200

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000222

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152252 Hom.: 2 Cov.: 34 AF XY: 0.000564 AC XY: 42 AN XY: 74444

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000703

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The c.560G>T (p.R187L) alteration is located in exon 1 (coding exon 1) of the MESP1 gene. This alteration results from a G to T substitution at nucleotide position 560, causing the arginine (R) at amino acid position 187 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 11, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with MESP1-related conditions. This variant is present in population databases (rs556672934, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 187 of the MESP1 protein (p.Arg187Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	0.94
Dann	Benign	0.78
DEOGEN2	Benign	0.096	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.095
Sift	Benign	0.44	T
Sift4G	Benign	0.36	T
Polyphen		0.0050	B
Vest4		0.27
MutPred		0.39		Loss of MoRF binding (P = 0.0099);
MVP		0.16
MPC		0.59
ClinPred		0.0083	T
GERP RS		0.93
Varity_R		0.052
gMVP		0.21

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: rs556672934; hg19: chr15-90293903;