12-48106148-A-T

Variant names:

• chr12-48106148-A-T
• rs4760619
• NM_001354735.1:c.-114A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001354735.1(PFKM):​c.-114A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 702,158 control chromosomes in the GnomAD database, including 7,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1392 hom., cov: 32)
  • Exomes 𝑓: 0.14 (6017 hom.)
• Consequence: PFKM NM_001354735.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.318
• Publications: 8 publications found

Genes affected

PFKM (HGNC:8877): (phosphofructokinase, muscle) Three phosphofructokinase isozymes exist in humans: muscle, liver and platelet. These isozymes function as subunits of the mammalian tetramer phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. Tetramer composition varies depending on tissue type. This gene encodes the muscle-type isozyme. Mutations in this gene have been associated with glycogen storage disease type VII, also known as Tarui disease. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]

SENP1 (HGNC:17927): (SUMO specific peptidase 1) This gene encodes a cysteine protease that specifically targets members of the small ubiquitin-like modifier (SUMO) protein family. This protease regulates SUMO pathways by deconjugating sumoylated proteins. This protease also functions to process the precursor SUMO proteins into their mature form. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-48106148-A-T is Benign according to our data. Variant chr12-48106148-A-T is described in ClinVar as [Benign]. Clinvar id is 1239017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SENP1	NM_001267594.2	c.-165T>A		upstream_gene_variant		ENST00000549518.6	NP_001254523.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SENP1	ENST00000549518.6	c.-165T>A		upstream_gene_variant		1	NM_001267594.2	ENSP00000447328.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17879 AN: 152150 Hom.: 1391 Cov.: 32

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.0621

Gnomad FIN AF: 0.0824

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.131 AC: 16903 AN: 129454 AF XY: 0.128

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.0953

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.248

Gnomad FIN exome AF: 0.0985

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.139 AC: 76327 AN: 549890 Hom.: 6017 Cov.: 0 AF XY: 0.135 AC XY: 40156 AN XY: 297686

African (AFR) AF: 0.0330 AC: 521 AN: 15786

American (AMR) AF: 0.0980 AC: 3399 AN: 34670

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 4361 AN: 20000

East Asian (EAS) AF: 0.215 AC: 6884 AN: 32084

South Asian (SAS) AF: 0.0553 AC: 3470 AN: 62750

European-Finnish (FIN) AF: 0.0932 AC: 3117 AN: 33432

Middle Eastern (MID) AF: 0.148 AC: 603 AN: 4064

European-Non Finnish (NFE) AF: 0.156 AC: 49504 AN: 316546

Other (OTH) AF: 0.146 AC: 4468 AN: 30558

GnomAD4 genome AF: 0.117 AC: 17873 AN: 152268 Hom.: 1392 Cov.: 32 AF XY: 0.114 AC XY: 8468 AN XY: 74462

African (AFR) AF: 0.0320 AC: 1328 AN: 41560

American (AMR) AF: 0.136 AC: 2078 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 792 AN: 3468

East Asian (EAS) AF: 0.235 AC: 1213 AN: 5172

South Asian (SAS) AF: 0.0620 AC: 299 AN: 4826

European-Finnish (FIN) AF: 0.0824 AC: 875 AN: 10614

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.161 AC: 10930 AN: 68008

Other (OTH) AF: 0.141 AC: 297 AN: 2110

Alfa AF: 0.145 Hom.: 333

Bravo AF: 0.119

Asia WGS AF: 0.107 AC: 371 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.9
DANN	Benign	0.79
PhyloP100		-0.32
PromoterAI		-0.046	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4760619; hg19: chr12-48499931;