rs139599055

Variant names:

• chr15-89776347-G-A
• rs139599055
• NM_001039958.2:c.-11G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039958.2(MESP2):​c.-11G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,530,920 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (8 hom., cov: 33)
  • Exomes 𝑓: 0.011 (98 hom.)
• Consequence: MESP2 NM_001039958.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.463
• Publications: 0 publications found

Genes affected

MESP2 (HGNC:29659): (mesoderm posterior bHLH transcription factor 2) This gene encodes a member of the bHLH family of transcription factors and plays a key role in defining the rostrocaudal patterning of somites via interactions with multiple Notch signaling pathways. This gene is expressed in the anterior presomitic mesoderm and is downregulated immediately after the formation of segmented somites. This gene also plays a role in the formation of epithelial somitic mesoderm and cardiac mesoderm. Mutations in the MESP2 gene cause autosomal recessive spondylocostal dystosis 2 (SCD02). [provided by RefSeq, Oct 2008]

MESP2 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 2, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124903550 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-89776347-G-A is Benign according to our data. Variant chr15-89776347-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 257238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00837 (1275/152368) while in subpopulation NFE AF = 0.0128 (868/68034). AF 95% confidence interval is 0.0121. There are 8 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039958.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MESP2	NM_001039958.2	MANE Select	c.-11G>A		5_prime_UTR	Exon 1 of 2	NP_001035047.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MESP2	ENST00000341735.5	TSL:1 MANE Select	c.-11G>A		5_prime_UTR	Exon 1 of 2	ENSP00000342392.3
	MESP2	ENST00000560219.2	TSL:1	c.31-1718G>A		intron	N/A	ENSP00000452998.1
	MESP2	ENST00000558723.1	TSL:3	n.39-1718G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00837 AC: 1275 AN: 152250 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00706

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00882 AC: 1109 AN: 125702 AF XY: 0.00898

Gnomad AFR exome AF: 0.00151

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.0308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00869

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0106 AC: 14629 AN: 1378552 Hom.: 98 Cov.: 30 AF XY: 0.0105 AC XY: 7129 AN XY: 680428

African (AFR) AF: 0.00146 AC: 45 AN: 30810

American (AMR) AF: 0.00493 AC: 175 AN: 35466

Ashkenazi Jewish (ASJ) AF: 0.0307 AC: 769 AN: 25048

East Asian (EAS) AF: 0.0000284 AC: 1 AN: 35254

South Asian (SAS) AF: 0.00243 AC: 191 AN: 78516

European-Finnish (FIN) AF: 0.00817 AC: 280 AN: 34286

Middle Eastern (MID) AF: 0.0140 AC: 57 AN: 4058

European-Non Finnish (NFE) AF: 0.0116 AC: 12480 AN: 1077516

Other (OTH) AF: 0.0110 AC: 631 AN: 57598

GnomAD4 genome AF: 0.00837 AC: 1275 AN: 152368 Hom.: 8 Cov.: 33 AF XY: 0.00816 AC XY: 608 AN XY: 74514

African (AFR) AF: 0.00151 AC: 63 AN: 41594

American (AMR) AF: 0.00705 AC: 108 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4834

European-Finnish (FIN) AF: 0.00706 AC: 75 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0128 AC: 868 AN: 68034

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0137 Hom.: 6

Bravo AF: 0.00787

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spondylocostal dysostosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.2
DANN	Benign	0.71
PhyloP100		-0.46
PromoterAI		0.035	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs139599055; hg19: chr15-90319578;