Genetic Variant PRAMEF6:p.Asp137His (chr1-12941444-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001010889.2(PRAMEF6):c.409G>C(p.Asp137His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,370,322 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000031 ( 1 hom., cov: 13)

Exomes 𝑓: 0.00013 ( 6 hom. )

Failed GnomAD Quality Control

Consequence

PRAMEF6
NM_001010889.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.96

Publications

1 publications found

Variant links:

Genes affected

PRAMEF6 (HGNC:30583): (PRAME family member 6) Enables ubiquitin ligase-substrate adaptor activity. Involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

PRAMEF6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.061588705).

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010889.2. 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
	PRAMEF6	NM_001010889.2	MANE Select	c.409G>C	p.Asp137His	missense	Exon 3 of 4	NP_001010889.1	Q5VXH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRAMEF6	ENST00000376189.5	TSL:1 MANE Select	c.409G>C	p.Asp137His	missense	Exon 3 of 4	ENSP00000365360.1	Q5VXH4
	PRAMEF6	ENST00000415464.6	TSL:1	c.409G>C	p.Asp137His	missense	Exon 3 of 4	ENSP00000401281.2	Q5VXH4

Frequencies

GnomAD3 genomes

AF:

0.0000315

AC:

AN:

95274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000567

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000200

AC:

AN:

250562

AF XY:

0.0000221

show subpopulations

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:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

181

AN:

1370322

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

682380

show subpopulations

African (AFR)

AF:

0.0000351

AC:

AN:

28512

American (AMR)

AF:

0.00

AC:

AN:

41120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23802

East Asian (EAS)

AF:

0.00

AC:

AN:

35888

South Asian (SAS)

AF:

0.00

AC:

AN:

81906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4248

European-Non Finnish (NFE)

AF:

0.000151

AC:

159

AN:

1050036

Other (OTH)

AF:

0.000375

AC:

AN:

55936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000315

AC:

AN:

95274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

45694

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13418

American (AMR)

AF:

0.00

AC:

AN:

10096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2592

East Asian (EAS)

AF:

0.00

AC:

AN:

3950

South Asian (SAS)

AF:

0.00

AC:

AN:

2726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

198

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

52884

Other (OTH)

AF:

0.00

AC:

AN:

1376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000192

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.55

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.075

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0014

M_CAP

Benign

0.0011

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-2.0

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.017

Sift

Uncertain

0.011

Sift4G

Benign

0.095

Polyphen

0.0060

Vest4

0.047

MutPred

0.31

Loss of loop (P = 0.0374)

MVP

0.043

MPC

1.9

ClinPred

0.045

GERP RS

-1.4

Varity_R

0.084

gMVP

0.27

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over