chr21-46235113-A-T

Variant names:

• chr21-46235113-A-T
• rs2298695
• ENST00000420074.1:n.1607A>T

Variant summary

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

The ENST00000420074.1(MCM3AP-AS1):​n.1607A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 686,950 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: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: MCM3AP-AS1 ENST00000420074.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140
• Publications: 0 publications found

Genes affected

MCM3AP-AS1 (HGNC:16417): (MCM3AP antisense RNA 1)

MCM3AP (HGNC:6946): (minichromosome maintenance complex component 3 associated protein) The minichromosome maintenance protein 3 (MCM3) is one of the MCM proteins essential for the initiation of DNA replication. The protein encoded by this gene is a MCM3 binding protein. It was reported to have phosphorylation-dependent DNA-primase activity, which was up-regulated in antigen immunization induced germinal center. This protein was demonstrated to be an acetyltransferase that acetylates MCM3 and plays a role in DNA replication. The mutagenesis of a nuclear localization signal of MCM3 affects the binding of this protein with MCM3, suggesting that this protein may also facilitate MCM3 nuclear localization. This gene is expressed in the brain or in neuronal tissue. An allelic variant encoding amino acid Lys at 915, instead of conserved Glu, has been identified in patients with mild intellectual disability. [provided by RefSeq, Jan 2014]

MCM3AP Gene-Disease associations (from GenCC):

• peripheral neuropathy, autosomal recessive, with or without impaired intellectual development

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

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=-0.68).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000420074.1. 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
	MCM3AP-AS1	NR_002776.4		n.37-5721A>T		intron	N/A
	MCM3AP-AS1	NR_110565.1		n.237+4586A>T		intron	N/A
	MCM3AP-AS1	NR_110566.1		n.37-1111A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM3AP-AS1	ENST00000420074.1	TSL:1	n.1607A>T		non_coding_transcript_exon	Exon 2 of 2
	MCM3AP-AS1	ENST00000455567.2	TSL:1	n.72-5721A>T		intron	N/A
	MCM3AP-AS1	ENST00000414659.5	TSL:2	n.237+4586A>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000146 AC: 1 AN: 686950 Hom.: 0 Cov.: 9 AF XY: 0.00000285 AC XY: 1 AN XY: 350512

⚠️ 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: 16884

American (AMR) AF: 0.00 AC: 0 AN: 19624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15230

East Asian (EAS) AF: 0.00 AC: 0 AN: 32080

South Asian (SAS) AF: 0.0000202 AC: 1 AN: 49512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2458

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 485582

Other (OTH) AF: 0.00 AC: 0 AN: 33606

⚠️ 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
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.9
DANN	Benign	0.91
PhyloP100		0.14

Splicing

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

Other links and lift over

dbSNP: rs2298695; hg19: chr21-47655027;