15-89750672-CGCCCCT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_018670.4(MESP1):c.554_559del(p.Gln185_Gly186del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,356,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: MESP1 NM_018670.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.659

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_018670.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP1	NM_018670.4	c.554_559del	p.Gln185_Gly186del	inframe_deletion	1/2	ENST00000300057.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP1	ENST00000300057.5	c.554_559del	p.Gln185_Gly186del	inframe_deletion	1/2	1	NM_018670.4	P1
MESP1	ENST00000559894.1	n.114+346_114+351del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152144 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000573

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000185 AC: 1 AN: 5402 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3052

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000347

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000355 AC: 427 AN: 1204358 Hom.: 0 AF XY: 0.000388 AC XY: 226 AN XY: 582302

Gnomad4 AFR exome AF: 0.000126

Gnomad4 AMR exome AF: 0.0000999

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000361

Gnomad4 SAS exome AF: 0.0000592

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000406

Gnomad4 OTH exome AF: 0.000242

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152252 Hom.: 0 Cov.: 34 AF XY: 0.000309 AC XY: 23 AN XY: 74444

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000574

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000242

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 11, 2023

This variant, c.554_559del, results in the deletion of 2 amino acid(s) of the MESP1 protein (p.Gln185_Gly186del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs755963854, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MESP1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs755963854; hg19: chr15-90293903;