chr1-12938736-C-T

Variant names:

• chr1-12938736-C-T
• rs77498625
• NM_001010889.2:c.1370G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001010889.2(PRAMEF6):​c.1370G>A​(p.Cys457Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 130,902 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (37 hom., cov: 22)
  • Exomes 𝑓: 0.084 (470 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRAMEF6 NM_001010889.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.09
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057281554).
• BP6: Variant 1-12938736-C-T is Benign according to our data. Variant chr1-12938736-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2327228.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 37 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.1370G>A	p.Cys457Tyr	missense	Exon 4 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.1370G>A	p.Cys457Tyr	missense	Exon 4 of 4	ENSP00000365360.1	Q5VXH4
	PRAMEF6	ENST00000415464.6	TSL:1	c.1370G>A	p.Cys457Tyr	missense	Exon 4 of 4	ENSP00000401281.2	Q5VXH4

Frequencies

GnomAD3 genomes AF: 0.112 AC: 14685 AN: 130802 Hom.: 38 Cov.: 22

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0370

Gnomad AMR AF: 0.0886

Gnomad ASJ AF: 0.0993

Gnomad EAS AF: 0.0756

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0665

Gnomad MID AF: 0.0913

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.00249 AC: 100 AN: 40140 AF XY: 0.00264

Gnomad AFR exome AF: 0.00658

Gnomad AMR exome AF: 0.00719

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00159

Gnomad OTH exome AF: 0.000707

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0836 AC: 102100 AN: 1221318 Hom.: 470 Cov.: 31 AF XY: 0.0857 AC XY: 52179 AN XY: 608656

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

African (AFR) AF: 0.105 AC: 3045 AN: 28930

American (AMR) AF: 0.0564 AC: 2310 AN: 40952

Ashkenazi Jewish (ASJ) AF: 0.0976 AC: 2243 AN: 22982

East Asian (EAS) AF: 0.0697 AC: 2520 AN: 36144

South Asian (SAS) AF: 0.0977 AC: 7150 AN: 73182

European-Finnish (FIN) AF: 0.0888 AC: 4342 AN: 48912

Middle Eastern (MID) AF: 0.130 AC: 617 AN: 4734

European-Non Finnish (NFE) AF: 0.0820 AC: 74975 AN: 914366

Other (OTH) AF: 0.0958 AC: 4898 AN: 51116

⚠️ 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: 0.112 AC: 14695 AN: 130902 Hom.: 37 Cov.: 22 AF XY: 0.110 AC XY: 7017 AN XY: 64056

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

African (AFR) AF: 0.126 AC: 4577 AN: 36196

American (AMR) AF: 0.0884 AC: 1179 AN: 13336

Ashkenazi Jewish (ASJ) AF: 0.0993 AC: 303 AN: 3052

East Asian (EAS) AF: 0.0754 AC: 320 AN: 4242

South Asian (SAS) AF: 0.119 AC: 477 AN: 3998

European-Finnish (FIN) AF: 0.0665 AC: 623 AN: 9372

Middle Eastern (MID) AF: 0.0897 AC: 21 AN: 234

European-Non Finnish (NFE) AF: 0.120 AC: 6956 AN: 57850

Other (OTH) AF: 0.117 AC: 208 AN: 1784

⚠️ 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: 0.147 Hom.: 8

ExAC AF: 0.000558 AC: 5

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.12
DANN	Benign	0.28
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00079	N
M_CAP	Benign	0.00097	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.72	N
PhyloP100		-1.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.044
Sift	Benign	0.22	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.036
MutPred		0.38		Gain of catalytic residue at L452 (P = 0.0797)
MVP		0.043
MPC		2.4
ClinPred		0.0024	T
GERP RS		0.17
Varity_R		0.039
gMVP		0.16
Mutation Taster		=100/0	polymorphism

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: rs77498625; hg19: chr1-12998566;