Genetic Variant MESP1:p.Leu61Pro (chr15-89751050-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018670.4(MESP1):c.182T>C(p.Leu61Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000085 in 1,176,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L61R) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Consequence

MESP1
NM_018670.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.79

Publications

0 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061225325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MESP1	NM_018670.4 link	c.182T>C	p.Leu61Pro	missense_variant	Exon 1 of 2	ENST00000300057.5	NP_061140.1	Q9BRJ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MESP1	ENST00000300057.5 link	c.182T>C	p.Leu61Pro	missense_variant	Exon 1 of 2	1	NM_018670.4	ENSP00000300057.4		Q9BRJ9
MESP1	ENST00000559894.1 link	n.88T>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.50e-7

AC:

AN:

1176066

Hom.:

Cov.:

AF XY:

0.00000176

AC XY:

AN XY:

568190

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23648

American (AMR)

AF:

0.00

AC:

AN:

9264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16002

East Asian (EAS)

AF:

0.00

AC:

AN:

27882

South Asian (SAS)

AF:

0.00

AC:

AN:

42390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3512

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

977306

Other (OTH)

AF:

0.00

AC:

AN:

48118

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.9

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.11

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.14

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.061

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-2.8

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.070

REVEL

Benign

0.089

Sift

Benign

0.31

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.037

MutPred

0.25

Gain of relative solvent accessibility (P = 0.0249);

MVP

0.12

MPC

0.72

ClinPred

0.076

GERP RS

-1.6

PromoterAI

0.049

Neutral

(source)

Varity_R

0.047

gMVP

0.29

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over