NM_005859.5:c.141_146dupCGGCGG

Variant names:

• chr5-140114310-T-TGGCGGC
• rs754074166
• NM_005859.5:c.141_146dupCGGCGG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_005859.5(PURA):​c.141_146dupCGGCGG​(p.Gly48_Gly49dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000612 in 1,291,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G49G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: PURA NM_005859.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.895
• Publications: 1 publications found

Genes affected

PURA (HGNC:9701): (purine rich element binding protein A) This gene product is a sequence-specific, single-stranded DNA-binding protein. It binds preferentially to the single strand of the purine-rich element termed PUR, which is present at origins of replication and in gene flanking regions in a variety of eukaryotes from yeasts through humans. Thus, it is implicated in the control of both DNA replication and transcription. Deletion of this gene has been associated with myelodysplastic syndrome and acute myelogenous leukemia. [provided by RefSeq, Jul 2008]

MALINC1 (HGNC:49009): (mitosis associated long intergenic non-coding RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 5-140114310-T-TGGCGGC is Benign according to our data. Variant chr5-140114310-T-TGGCGGC is described in ClinVar as Likely_benign. ClinVar VariationId is 542077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005859.5. 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
	PURA	NM_005859.5	MANE Select	c.141_146dupCGGCGG	p.Gly48_Gly49dup	disruptive_inframe_insertion	Exon 1 of 1	NP_005850.1	Q00577

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PURA	ENST00000331327.5	TSL:6 MANE Select	c.141_146dupCGGCGG	p.Gly48_Gly49dup	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000332706.3	Q00577
	PURA	ENST00000651386.1		c.141_146dupCGGCGG	p.Gly48_Gly49dup	disruptive_inframe_insertion	Exon 2 of 2	ENSP00000499133.1	Q00577
	PURA	ENST00000505703.2	TSL:3	c.141_146dupCGGCGG	p.Gly48_Gly49dup	disruptive_inframe_insertion	Exon 2 of 2	ENSP00000498560.1	A0A494C0H6

Frequencies

GnomAD3 genomes AF: 0.0000860 AC: 12 AN: 139490 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00212

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000789

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000685 AC: 2 AN: 29190 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000554

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000672

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000582 AC: 67 AN: 1151502 Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 33 AN XY: 558774

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

African (AFR) AF: 0.000125 AC: 3 AN: 24018

American (AMR) AF: 0.000188 AC: 2 AN: 10644

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 18 AN: 16790

East Asian (EAS) AF: 0.00 AC: 0 AN: 28132

South Asian (SAS) AF: 0.00 AC: 0 AN: 32896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3626

European-Non Finnish (NFE) AF: 0.0000425 AC: 41 AN: 964468

Other (OTH) AF: 0.0000645 AC: 3 AN: 46496

⚠️ 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 AF: 0.0000860 AC: 12 AN: 139578 Hom.: 0 Cov.: 32 AF XY: 0.0000884 AC XY: 6 AN XY: 67850

African (AFR) AF: 0.00 AC: 0 AN: 37576

American (AMR) AF: 0.00 AC: 0 AN: 14350

Ashkenazi Jewish (ASJ) AF: 0.00212 AC: 7 AN: 3298

East Asian (EAS) AF: 0.00 AC: 0 AN: 4720

South Asian (SAS) AF: 0.00 AC: 0 AN: 4362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.0000789 AC: 5 AN: 63348

Other (OTH) AF: 0.00 AC: 0 AN: 1932

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	PURA-related disorder (1)
-	-	1	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90
Mutation Taster		=78/22	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs754074166; hg19: chr5-139493895;