1-12938878-C-G

Variant names:

• chr1-12938878-C-G
• rs74702454
• NM_001010889.2:c.1228G>C

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.1228G>C​(p.Val410Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 136,156 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (46 hom., cov: 21)
  • Exomes 𝑓: 0.15 (881 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRAMEF6 NM_001010889.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.311
• Publications: 2 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=0.003136903).
• BP6: Variant 1-12938878-C-G is Benign according to our data. Variant chr1-12938878-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2404504.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 46 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.1228G>C	p.Val410Leu	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.1228G>C	p.Val410Leu	missense	Exon 4 of 4	ENSP00000365360.1	Q5VXH4
	PRAMEF6	ENST00000415464.6	TSL:1	c.1228G>C	p.Val410Leu	missense	Exon 4 of 4	ENSP00000401281.2	Q5VXH4

Frequencies

GnomAD3 genomes AF: 0.132 AC: 18021 AN: 136048 Hom.: 47 Cov.: 21

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.0566

Gnomad AMR AF: 0.0997

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.0900

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0924

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.00653 AC: 254 AN: 38902 AF XY: 0.00593

Gnomad AFR exome AF: 0.00282

Gnomad AMR exome AF: 0.00316

Gnomad ASJ exome AF: 0.00180

Gnomad EAS exome AF: 0.00189

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00709

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.150 AC: 209119 AN: 1398094 Hom.: 881 Cov.: 57 AF XY: 0.150 AC XY: 104365 AN XY: 695312

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

African (AFR) AF: 0.148 AC: 4767 AN: 32174

American (AMR) AF: 0.0816 AC: 3537 AN: 43354

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3264 AN: 25062

East Asian (EAS) AF: 0.0871 AC: 3230 AN: 37098

South Asian (SAS) AF: 0.147 AC: 12040 AN: 81792

European-Finnish (FIN) AF: 0.116 AC: 5957 AN: 51482

Middle Eastern (MID) AF: 0.177 AC: 847 AN: 4792

European-Non Finnish (NFE) AF: 0.157 AC: 166791 AN: 1064714

Other (OTH) AF: 0.151 AC: 8686 AN: 57626

⚠️ 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: 0.132 AC: 18037 AN: 136156 Hom.: 46 Cov.: 21 AF XY: 0.130 AC XY: 8644 AN XY: 66588

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

African (AFR) AF: 0.135 AC: 5061 AN: 37382

American (AMR) AF: 0.0994 AC: 1363 AN: 13706

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 367 AN: 3180

East Asian (EAS) AF: 0.0893 AC: 392 AN: 4388

South Asian (SAS) AF: 0.135 AC: 559 AN: 4134

European-Finnish (FIN) AF: 0.0924 AC: 897 AN: 9712

Middle Eastern (MID) AF: 0.133 AC: 33 AN: 248

European-Non Finnish (NFE) AF: 0.149 AC: 9061 AN: 60682

Other (OTH) AF: 0.137 AC: 255 AN: 1858

⚠️ 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: 0.00 Hom.: 0

ExAC AF: 0.000884 AC: 2

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	0.075
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.017
DANN	Benign	0.079
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-2.9
Eigen_PC	Benign	-2.9
FATHMM_MKL	Benign	0.00012	N
M_CAP	Benign	0.00047	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-0.31
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.97	N
REVEL	Benign	0.071
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0080
MutPred		0.37		Gain of catalytic residue at V410 (P = 0.0452)
MVP		0.043
MPC		1.6
ClinPred		0.000065	T
GERP RS		-2.6
Varity_R		0.033
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74702454; hg19: chr1-12998708;