15-89750729-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018670.4(MESP1):c.503A>G(p.Asp168Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,413,792 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (20 hom., cov: 34)
  • Exomes 𝑓: 0.00073 (14 hom.)
• Consequence: MESP1 NM_018670.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.279

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=0.0040051043).
• BP6: Variant 15-89750729-T-C is Benign according to our data. Variant chr15-89750729-T-C is described in ClinVar as [Benign]. Clinvar id is 1654286.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 = 0.00785 (1194/152026) while in subpopulation AFR AF= 0.0278 (1151/41474). AF 95% confidence interval is 0.0264. There are 20 homozygotes in gnomad4. There are 561 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP1	NM_018670.4	c.503A>G	p.Asp168Gly	missense_variant	1/2	ENST00000300057.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP1	ENST00000300057.5	c.503A>G	p.Asp168Gly	missense_variant	1/2	1	NM_018670.4	P1
MESP1	ENST00000559894.1	n.114+295A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00785 AC: 1193 AN: 151916 Hom.: 20 Cov.: 34

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00127 AC: 83 AN: 65276 Hom.: 1 AF XY: 0.00114 AC XY: 43 AN XY: 37862

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.000893

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000373

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000298

Gnomad OTH exome AF: 0.000760

GnomAD4 exome AF: 0.000733 AC: 925 AN: 1261766 Hom.: 14 Cov.: 67 AF XY: 0.000635 AC XY: 391 AN XY: 615946

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000588

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.00785 AC: 1194 AN: 152026 Hom.: 20 Cov.: 34 AF XY: 0.00755 AC XY: 561 AN XY: 74342

Gnomad4 AFR AF: 0.0278

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00652 Hom.: 2

Bravo AF: 0.00910

ESP6500AA AF: 0.0114 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00126 AC: 141

Asia WGS AF: 0.000868 AC: 3 AN: 3470

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

Jun 12, 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

Aug 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.037
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.92	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.033	D
Polyphen		0.95	P
Vest4		0.17
MVP		0.41
MPC		1.5
ClinPred		0.034	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.32

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: rs200810210; hg19: chr15-90293960;