15-89750541-C-A

Variant names:

• chr15-89750541-C-A
• rs771795136
• NM_018670.4:c.691G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018670.4(MESP1):​c.691G>T​(p.Gly231Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000746 in 1,340,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. G231R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: MESP1 NM_018670.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.118
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13256937).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018670.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MESP1	NM_018670.4	MANE Select	c.691G>T	p.Gly231Trp	missense	Exon 1 of 2	NP_061140.1	Q9BRJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MESP1	ENST00000300057.5	TSL:1 MANE Select	c.691G>T	p.Gly231Trp	missense	Exon 1 of 2	ENSP00000300057.4	Q9BRJ9
	MESP1	ENST00000559894.1	TSL:2	n.115-314G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.46e-7 AC: 1 AN: 1340318 Hom.: 0 Cov.: 35 AF XY: 0.00000152 AC XY: 1 AN XY: 658832

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

African (AFR) AF: 0.00 AC: 0 AN: 29124

American (AMR) AF: 0.00 AC: 0 AN: 30314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20494

East Asian (EAS) AF: 0.00 AC: 0 AN: 36098

South Asian (SAS) AF: 0.00 AC: 0 AN: 70666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4766

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061192

Other (OTH) AF: 0.00 AC: 0 AN: 55328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.12
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.083	T
Polyphen		0.063	B
Vest4		0.32
MutPred		0.18		Gain of glycosylation at P236 (P = 0.1474)
MVP		0.18
MPC		1.2
ClinPred		0.40	T
GERP RS		0.28
Varity_R		0.049
gMVP		0.12
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs771795136; hg19: chr15-90293772;