8-143824349-TGCCGCCGCC-TGCCGCCGCCGCC

Variant names:

• chr8-143824349-T-TGCC
• rs540307276
• NM_078480.3:c.72_74dupGGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_078480.3(PUF60):​c.72_74dupGGC​(p.Ala25dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,612,306 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: PUF60 NM_078480.3 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.42
• Publications: 0 publications found

Genes affected

PUF60 (HGNC:17042): (poly(U) binding splicing factor 60) This gene encodes a nucleic acid-binding protein that plays a role in a variety of nuclear processes, including pre-mRNA splicing and transcriptional regulation. The encoded protein forms a complex with the far upstream DNA element (FUSE) and FUSE-binding protein at the myelocytomatosis oncogene (MYC) promoter. This complex represses MYC transcription through the core-TFIIH basal transcription factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

PUF60 Gene-Disease associations (from GenCC):

• 8q24.3 microdeletion syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_078480.3
• BP6: Variant 8-143824349-T-TGCC is Benign according to our data. Variant chr8-143824349-T-TGCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 599475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00106 (162/152258) while in subpopulation AFR AF = 0.00337 (140/41550). AF 95% confidence interval is 0.00291. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 162 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_078480.3. 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
	PUF60	NM_078480.3	MANE Select	c.72_74dupGGC	p.Ala25dup	disruptive_inframe_insertion	Exon 2 of 12	NP_510965.1	Q9UHX1-1
	PUF60	NM_001362895.2		c.183_185dupGGC	p.Ala62dup	disruptive_inframe_insertion	Exon 3 of 13	NP_001349824.1	E9PL19
	PUF60	NM_001362896.2		c.183_185dupGGC	p.Ala62dup	disruptive_inframe_insertion	Exon 3 of 13	NP_001349825.1	E9PL19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUF60	ENST00000526683.6	TSL:1 MANE Select	c.72_74dupGGC	p.Ala25dup	disruptive_inframe_insertion	Exon 2 of 12	ENSP00000434359.1	Q9UHX1-1
	PUF60	ENST00000349157.10	TSL:1	c.72_74dupGGC	p.Ala25dup	disruptive_inframe_insertion	Exon 2 of 11	ENSP00000322036.7	Q9UHX1-2
	PUF60	ENST00000453551.6	TSL:1	c.-58_-56dupGGC		5_prime_UTR	Exon 2 of 12	ENSP00000402953.2	Q9UHX1-3

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000528 AC: 127 AN: 240516 AF XY: 0.000357

Gnomad AFR exome AF: 0.00347

Gnomad AMR exome AF: 0.000792

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.000374 AC: 546 AN: 1460048 Hom.: 1 Cov.: 31 AF XY: 0.000352 AC XY: 256 AN XY: 726358

African (AFR) AF: 0.00272 AC: 91 AN: 33470

American (AMR) AF: 0.000806 AC: 36 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86236

European-Finnish (FIN) AF: 0.0000383 AC: 2 AN: 52226

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.000349 AC: 388 AN: 1111636

Other (OTH) AF: 0.000282 AC: 17 AN: 60258

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74450

African (AFR) AF: 0.00337 AC: 140 AN: 41550

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67988

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.00120

EpiCase AF: 0.000164

EpiControl AF: 0.000535

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	8q24.3 microdeletion syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=85/15	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs540307276; hg19: chr8-144906519;