12-43754456-T-C

Variant names:

• chr12-43754456-T-C
• rs1057190
• NM_031292.5:c.790A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031292.5(PUS7L):​c.790A>G​(p.Lys264Glu) 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 1,613,506 control chromosomes in the GnomAD database, including 20,851 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (6452 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14399 hom.)
• Consequence: PUS7L NM_031292.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.67
• Publications: 31 publications found

Genes affected

PUS7L (HGNC:25276): (pseudouridine synthase 7 like) Predicted to enable pseudouridine synthase activity. Predicted to be involved in pseudouridine synthesis. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.487023E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUS7L	NM_031292.5	c.790A>G	p.Lys264Glu	missense_variant	Exon 2 of 9	ENST00000344862.10	NP_112582.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUS7L	ENST00000344862.10	c.790A>G	p.Lys264Glu	missense_variant	Exon 2 of 9	1	NM_031292.5	ENSP00000343081.5

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35045 AN: 152020 Hom.: 6425 Cov.: 33

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.0923

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0955

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.223

GnomAD2 exomes AF: 0.153 AC: 38353 AN: 251256 AF XY: 0.144

Gnomad AFR exome AF: 0.525

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.0971

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.122 AC: 178538 AN: 1461368 Hom.: 14399 Cov.: 33 AF XY: 0.121 AC XY: 88133 AN XY: 726984

African (AFR) AF: 0.526 AC: 17592 AN: 33448

American (AMR) AF: 0.153 AC: 6839 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 5044 AN: 26124

East Asian (EAS) AF: 0.145 AC: 5738 AN: 39674

South Asian (SAS) AF: 0.134 AC: 11562 AN: 86208

European-Finnish (FIN) AF: 0.101 AC: 5371 AN: 53412

Middle Eastern (MID) AF: 0.208 AC: 1199 AN: 5766

European-Non Finnish (NFE) AF: 0.105 AC: 116204 AN: 1111664

Other (OTH) AF: 0.149 AC: 8989 AN: 60376

GnomAD4 genome AF: 0.231 AC: 35110 AN: 152138 Hom.: 6452 Cov.: 33 AF XY: 0.227 AC XY: 16871 AN XY: 74412

African (AFR) AF: 0.513 AC: 21286 AN: 41466

American (AMR) AF: 0.174 AC: 2666 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 646 AN: 3472

East Asian (EAS) AF: 0.159 AC: 825 AN: 5184

South Asian (SAS) AF: 0.141 AC: 681 AN: 4830

European-Finnish (FIN) AF: 0.0955 AC: 1013 AN: 10604

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7385 AN: 67978

Other (OTH) AF: 0.220 AC: 465 AN: 2110

Alfa AF: 0.154 Hom.: 7922

Bravo AF: 0.249

TwinsUK AF: 0.0968 AC: 359

ALSPAC AF: 0.106 AC: 408

ESP6500AA AF: 0.513 AC: 2262

ESP6500EA AF: 0.115 AC: 990

ExAC AF: 0.158 AC: 19219

Asia WGS AF: 0.185 AC: 642 AN: 3478

EpiCase AF: 0.113

EpiControl AF: 0.112

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.51
DEOGEN2	Benign	0.000031	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.14	.;.;T
MetaRNN	Benign	0.000065	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.2	N;N;N
PhyloP100		2.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.41	N;N;N
REVEL	Benign	0.097
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.013
MPC		0.039
ClinPred		0.0069	T
GERP RS		5.3
Varity_R		0.072
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

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: rs1057190; hg19: chr12-44148259; COSMIC: COSV61262008; COSMIC: COSV61262008;