NM_002402.4:c.181+744G>T

Variant names:

• chr7-130496266-G-T
• rs3807348
• NM_002402.4:c.181+744G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002402.4(MEST):​c.181+744G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000363 in 275,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: MEST NM_002402.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0120
• Publications: 0 publications found

Genes affected

MEST (HGNC:7028): (mesoderm specific transcript) This gene encodes a member of the alpha/beta hydrolase superfamily. It is imprinted, exhibiting preferential expression from the paternal allele in fetal tissues, and isoform-specific imprinting in lymphocytes. The loss of imprinting of this gene has been linked to certain types of cancer and may be due to promotor switching. The encoded protein may play a role in development. Alternatively spliced transcript variants encoding multiple isoforms have been identified for this gene. Pseudogenes of this gene are located on the short arm of chromosomes 3 and 4, and the long arm of chromosomes 6 and 15. [provided by RefSeq, Dec 2011]

ENSG00000270823 (HGNC:):

MIR335 (HGNC:31773): (microRNA 335) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The encoded miRNA is dysregulated in a variety of cancers, including breast, colorectal, and prostate cancer. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002402.4. 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
	MEST	NM_002402.4	MANE Select	c.181+744G>T		intron	N/A	NP_002393.2
	MEST	NM_177524.2		c.154+744G>T		intron	N/A	NP_803490.1
	MEST	NM_177525.2		c.154+744G>T		intron	N/A	NP_803491.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEST	ENST00000223215.10	TSL:1 MANE Select	c.181+744G>T		intron	N/A	ENSP00000223215.4
	MEST	ENST00000341441.9	TSL:1	c.154+744G>T		intron	N/A	ENSP00000342749.4
	MEST	ENST00000416162.7	TSL:1	c.154+744G>T		intron	N/A	ENSP00000408933.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000363 AC: 1 AN: 275192 Hom.: 0 Cov.: 0 AF XY: 0.00000630 AC XY: 1 AN XY: 158752

⚠️ 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: 5638

American (AMR) AF: 0.00 AC: 0 AN: 14416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9756

East Asian (EAS) AF: 0.00 AC: 0 AN: 7790

South Asian (SAS) AF: 0.00 AC: 0 AN: 52562

European-Finnish (FIN) AF: 0.0000462 AC: 1 AN: 21628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1058

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 149734

Other (OTH) AF: 0.00 AC: 0 AN: 12610

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.37
DANN	Benign	0.40
PhyloP100		-0.012

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: rs3807348; hg19: chr7-130136107;