NM_016252.4:c.12291+620_12291+621insTGTGTGTGTGTGTGTGT

Variant names:

• chr2-32532171-G-GTGTGTGTGTGTGTGTGT
• rs35999329
• NM_016252.4:c.12291+620_12291+621insTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_016252.4(BIRC6):​c.12291+620_12291+621insTGTGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BIRC6 NM_016252.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.931
• Publications: 2 publications found

Genes affected

BIRC6 (HGNC:13516): (baculoviral IAP repeat containing 6) This gene encodes a protein with a BIR (baculoviral inhibition of apoptosis protein repeat) domain and a UBCc (ubiquitin-conjugating enzyme E2, catalytic) domain. This protein inhibits apoptosis by facilitating the degradation of apoptotic proteins by ubiquitination. [provided by RefSeq, Jul 2008]

MIR558 (HGNC:32814): (microRNA 558) 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 RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016252.4. 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
	BIRC6	NM_016252.4	MANE Select	c.12291+620_12291+621insTGTGTGTGTGTGTGTGT		intron	N/A	NP_057336.3
	MIR558	NR_030285.1		n.19_20insTGTGTGTGTGTGTGTGT		non_coding_transcript_exon	Exon 1 of 1
	BIRC6	NM_001378125.1		c.12288+620_12288+621insTGTGTGTGTGTGTGTGT		intron	N/A	NP_001365054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIRC6	ENST00000421745.7	TSL:1 MANE Select	c.12291+620_12291+621insTGTGTGTGTGTGTGTGT		intron	N/A	ENSP00000393596.2
	MIR558	ENST00000384920.1	TSL:6	n.19_20insTGTGTGTGTGTGTGTGT		non_coding_transcript_exon	Exon 1 of 1
	BIRC6	ENST00000700518.1		c.12240+620_12240+621insTGTGTGTGTGTGTGTGT		intron	N/A	ENSP00000515025.1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 152 AN: 149198 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000741

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000600

Gnomad ASJ AF: 0.00204

Gnomad EAS AF: 0.000990

Gnomad SAS AF: 0.00215

Gnomad FIN AF: 0.0000983

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00133

Gnomad OTH AF: 0.000488

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00161 AC: 603 AN: 375688 Hom.: 0 Cov.: 0 AF XY: 0.00158 AC XY: 339 AN XY: 214130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00224 AC: 23 AN: 10248

American (AMR) AF: 0.00179 AC: 64 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.00399 AC: 46 AN: 11518

East Asian (EAS) AF: 0.000999 AC: 13 AN: 13016

South Asian (SAS) AF: 0.00182 AC: 120 AN: 65934

European-Finnish (FIN) AF: 0.00211 AC: 67 AN: 31722

Middle Eastern (MID) AF: 0.000774 AC: 1 AN: 1292

European-Non Finnish (NFE) AF: 0.00131 AC: 249 AN: 189930

Other (OTH) AF: 0.00122 AC: 20 AN: 16350

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00102 AC: 153 AN: 149316 Hom.: 0 Cov.: 0 AF XY: 0.00107 AC XY: 78 AN XY: 72872

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000739 AC: 30 AN: 40616

American (AMR) AF: 0.000666 AC: 10 AN: 15008

Ashkenazi Jewish (ASJ) AF: 0.00204 AC: 7 AN: 3438

East Asian (EAS) AF: 0.000993 AC: 5 AN: 5036

South Asian (SAS) AF: 0.00215 AC: 10 AN: 4650

European-Finnish (FIN) AF: 0.0000983 AC: 1 AN: 10172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00133 AC: 89 AN: 67148

Other (OTH) AF: 0.000483 AC: 1 AN: 2072

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00698 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.93
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: rs35999329; hg19: chr2-32757238;