15-89750712-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_018670.4(MESP1):c.520A>G(p.Met174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,385,834 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: MESP1 NM_018670.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.622

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 -16 ACMG points.

• BP6: Variant 15-89750712-T-C is Benign according to our data. Variant chr15-89750712-T-C is described in ClinVar as [Benign]. Clinvar id is 1537845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1791/152244) while in subpopulation AFR AF= 0.0411 (1707/41572). AF 95% confidence interval is 0.0394. There are 39 homozygotes in gnomad4. There are 878 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 39 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP1	NM_018670.4	c.520A>G	p.Met174Val	missense_variant	1/2	ENST00000300057.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP1	ENST00000300057.5	c.520A>G	p.Met174Val	missense_variant	1/2	1	NM_018670.4	P1
MESP1	ENST00000559894.1	n.114+312A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1790 AN: 152136 Hom.: 39 Cov.: 34

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00280 AC: 122 AN: 43542 Hom.: 2 AF XY: 0.00215 AC XY: 54 AN XY: 25156

Gnomad AFR exome AF: 0.0429

Gnomad AMR exome AF: 0.00224

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: 0.00118

GnomAD4 exome AF: 0.00109 AC: 1350 AN: 1233590 Hom.: 28 Cov.: 66 AF XY: 0.000925 AC XY: 554 AN XY: 598984

Gnomad4 AFR exome AF: 0.0435

Gnomad4 AMR exome AF: 0.00287

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000179

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.0118 AC: 1791 AN: 152244 Hom.: 39 Cov.: 34 AF XY: 0.0118 AC XY: 878 AN XY: 74446

Gnomad4 AFR AF: 0.0411

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00867 Hom.: 1

Bravo AF: 0.0129

ESP6500AA AF: 0.0218 AC: 64

ESP6500EA AF: 0.000156 AC: 1

ExAC AF: 0.00197 AC: 214

Asia WGS AF: 0.00203 AC: 7 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

Feb 19, 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

Dec 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	5.8
Dann	Benign	0.62
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.18
Sift	Benign	0.21	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.050
MVP		0.27
MPC		0.45
ClinPred		0.0058	T
GERP RS		-5.8
Varity_R		0.037
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201582061; hg19: chr15-90293943;