rs2758357

Variant names:

• chr6-159713959-C-T
• rs2758357
• ENST00000403291.1:n.27G>A

Variant summary

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

The ENST00000403291.1(HNRNPH1P1):​n.27G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 790,188 control chromosomes in the GnomAD database, including 67,318 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (13691 hom., cov: 30)
  • Exomes 𝑓: 0.39 (53627 hom.)
• Consequence: HNRNPH1P1 ENST00000403291.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0620
• Publications: 6 publications found

Genes affected

HNRNPH1P1 (HGNC:48751): (heterogeneous nuclear ribonucleoprotein H1 pseudogene 1)

SOD2 (HGNC:11180): (superoxide dismutase 2) This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 1. [provided by RefSeq, Apr 2016]

SOD2 Gene-Disease associations (from GenCC):

• cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPH1P1		n.159713959C>T		intragenic_variant
SOD2	NM_001322817.2	c.-116+16926G>A		intron_variant	Intron 3 of 7		NP_001309746.1
SOD2	NM_001322819.2	c.-116+13307G>A		intron_variant	Intron 1 of 4		NP_001309748.1
SOD2	NM_001322820.2	c.-116+12893G>A		intron_variant	Intron 1 of 4		NP_001309749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPH1P1	ENST00000403291.1	n.27G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
SOD2	ENST00000545162.5	c.92+13307G>A		intron_variant	Intron 1 of 3	3		ENSP00000441362.1
SOD2	ENST00000535561.5	c.92+12893G>A		intron_variant	Intron 1 of 3	3		ENSP00000445015.1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61277 AN: 151674 Hom.: 13684 Cov.: 30

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.421

GnomAD4 exome AF: 0.390 AC: 248900 AN: 638396 Hom.: 53627 Cov.: 8 AF XY: 0.396 AC XY: 132096 AN XY: 333888

African (AFR) AF: 0.164 AC: 2913 AN: 17794

American (AMR) AF: 0.573 AC: 13196 AN: 23026

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 6176 AN: 13938

East Asian (EAS) AF: 0.155 AC: 5004 AN: 32290

South Asian (SAS) AF: 0.441 AC: 22369 AN: 50716

European-Finnish (FIN) AF: 0.467 AC: 21596 AN: 46222

Middle Eastern (MID) AF: 0.395 AC: 1509 AN: 3820

European-Non Finnish (NFE) AF: 0.391 AC: 163885 AN: 419564

Other (OTH) AF: 0.395 AC: 12252 AN: 31026

GnomAD4 genome AF: 0.404 AC: 61279 AN: 151792 Hom.: 13691 Cov.: 30 AF XY: 0.402 AC XY: 29847 AN XY: 74158

African (AFR) AF: 0.214 AC: 8880 AN: 41402

American (AMR) AF: 0.520 AC: 7928 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1714 AN: 3466

East Asian (EAS) AF: 0.180 AC: 926 AN: 5156

South Asian (SAS) AF: 0.470 AC: 2249 AN: 4782

European-Finnish (FIN) AF: 0.462 AC: 4863 AN: 10526

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33255 AN: 67902

Other (OTH) AF: 0.417 AC: 880 AN: 2110

Alfa AF: 0.444 Hom.: 2072

Bravo AF: 0.397

Asia WGS AF: 0.332 AC: 1154 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.3
DANN	Benign	0.70
PhyloP100		0.062
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: rs2758357; hg19: chr6-160134991; COSMIC: COSV67835003;