rs867646760

Variant names:

• chr8-143816962-G-A
• rs867646760
• NM_078480.3:c.1328C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-143816962-G-A
• chr8-143816962-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_078480.3(PUF60):​c.1328C>T​(p.Ser443Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,421,632 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S443S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PUF60 NM_078480.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27
• Publications: 3 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), PanelApp Australia, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1328C>T	p.Ser443Leu	missense	Exon 11 of 12	NP_510965.1	Q9UHX1-1
	PUF60	NM_001362895.2		c.1439C>T	p.Ser480Leu	missense	Exon 12 of 13	NP_001349824.1	E9PL19
	PUF60	NM_001362896.2		c.1439C>T	p.Ser480Leu	missense	Exon 12 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.1328C>T	p.Ser443Leu	missense	Exon 11 of 12	ENSP00000434359.1	Q9UHX1-1
	PUF60	ENST00000349157.10	TSL:1	c.1277C>T	p.Ser426Leu	missense	Exon 10 of 11	ENSP00000322036.7	Q9UHX1-2
	PUF60	ENST00000453551.6	TSL:1	c.1199C>T	p.Ser400Leu	missense	Exon 11 of 12	ENSP00000402953.2	Q9UHX1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 225454 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1421632 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 705910

African (AFR) AF: 0.00 AC: 0 AN: 32386

American (AMR) AF: 0.00 AC: 0 AN: 41772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24822

East Asian (EAS) AF: 0.00 AC: 0 AN: 37016

South Asian (SAS) AF: 0.00 AC: 0 AN: 84216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1088516

Other (OTH) AF: 0.00 AC: 0 AN: 58034

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.40
Sift	Benign	0.062	T
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.65
MutPred		0.21		Loss of glycosylation at S443 (P = 0.0283)
MVP		0.67
MPC		1.1
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.85
gMVP		0.87
Mutation Taster		=35/65	disease causing

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: rs867646760; hg19: chr8-144899132; COSMIC: COSV100253734; COSMIC: COSV100253734;