NM_018670.4:c.669C>G

Variant names:

• chr15-89750563-G-C
• rs2305440
• NM_018670.4:c.669C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018670.4(MESP1):​c.669C>G​(p.Phe223Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,465,286 control chromosomes in the GnomAD database, including 62,707 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5173 hom., cov: 35)
  • Exomes 𝑓: 0.29 (57534 hom.)
• Consequence: MESP1 NM_018670.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.256
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039317906).
• BP6: Variant 15-89750563-G-C is Benign according to our data. Variant chr15-89750563-G-C is described in ClinVar as Benign. ClinVar VariationId is 1629584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

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.669C>G	p.Phe223Leu	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.669C>G	p.Phe223Leu	missense	Exon 1 of 2	ENSP00000300057.4	Q9BRJ9
	MESP1	ENST00000559894.1	TSL:2	n.115-336C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38878 AN: 152040 Hom.: 5169 Cov.: 35

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.0954

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.218 AC: 17159 AN: 78758 AF XY: 0.226

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.0978

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.292 AC: 383049 AN: 1313138 Hom.: 57534 Cov.: 59 AF XY: 0.293 AC XY: 188451 AN XY: 643374

African (AFR) AF: 0.191 AC: 5306 AN: 27804

American (AMR) AF: 0.170 AC: 4498 AN: 26418

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 6894 AN: 19916

East Asian (EAS) AF: 0.0878 AC: 3000 AN: 34150

South Asian (SAS) AF: 0.291 AC: 19651 AN: 67436

European-Finnish (FIN) AF: 0.258 AC: 8101 AN: 31422

Middle Eastern (MID) AF: 0.407 AC: 1854 AN: 4550

European-Non Finnish (NFE) AF: 0.304 AC: 318289 AN: 1047202

Other (OTH) AF: 0.285 AC: 15456 AN: 54240

GnomAD4 genome AF: 0.256 AC: 38909 AN: 152148 Hom.: 5173 Cov.: 35 AF XY: 0.253 AC XY: 18792 AN XY: 74360

African (AFR) AF: 0.203 AC: 8416 AN: 41542

American (AMR) AF: 0.222 AC: 3402 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1215 AN: 3470

East Asian (EAS) AF: 0.0957 AC: 493 AN: 5150

South Asian (SAS) AF: 0.291 AC: 1404 AN: 4828

European-Finnish (FIN) AF: 0.254 AC: 2694 AN: 10590

Middle Eastern (MID) AF: 0.360 AC: 105 AN: 292

European-Non Finnish (NFE) AF: 0.301 AC: 20441 AN: 67944

Other (OTH) AF: 0.276 AC: 585 AN: 2116

Alfa AF: 0.275 Hom.: 1174

Bravo AF: 0.250

TwinsUK AF: 0.298 AC: 1104

ALSPAC AF: 0.291 AC: 1121

ESP6500AA AF: 0.143 AC: 435

ESP6500EA AF: 0.220 AC: 1383

ExAC AF: 0.189 AC: 19070

Asia WGS AF: 0.179 AC: 621 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MESP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.6
DANN	Benign	0.84
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.26
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.062
Sift	Benign	0.23	T
Sift4G	Benign	0.65	T
Polyphen		0.0010	B
Vest4		0.088
MutPred		0.32		Loss of loop (P = 0.0203)
MPC		0.53
ClinPred		0.0025	T
GERP RS		0.42
Varity_R		0.054
gMVP		0.093
Mutation Taster		=99/1	polymorphism (auto)

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: rs2305440; hg19: chr15-90293794; COSMIC: COSV107354398; COSMIC: COSV107354398;