rs1056663

chr7-47965365-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004507.4(HUS1):c.834G>A(p.Ala278=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 1,605,974 control chromosomes in the GnomAD database, including 203,921 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 0.46 (16801 hom., cov: 33)
  • Exomes 𝑓: 0.50 (187120 hom.)
• Consequence: HUS1 NM_004507.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.24

Genes affected

HUS1 (HGNC:5309): (HUS1 checkpoint clamp component) The protein encoded by this gene is a component of an evolutionarily conserved, genotoxin-activated checkpoint complex that is involved in the cell cycle arrest in response to DNA damage. This protein forms a heterotrimeric complex with checkpoint proteins RAD9 and RAD1. In response to DNA damage, the trimeric complex interacts with another protein complex consisting of checkpoint protein RAD17 and four small subunits of the replication factor C (RFC), which loads the combined complex onto the chromatin. The DNA damage induced chromatin binding has been shown to depend on the activation of the checkpoint kinase ATM, and is thought to be an early checkpoint signaling event. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=-2.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUS1	NM_004507.4	c.834G>A	p.Ala278=	synonymous_variant	8/8	ENST00000258774.10
HUS1	NM_001363683.2	c.771G>A	p.Ala257=	synonymous_variant	8/8
HUS1	NR_037917.2	n.988G>A		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUS1	ENST00000258774.10	c.834G>A	p.Ala278=	synonymous_variant	8/8	1	NM_004507.4	P1
HUS1	ENST00000432325.5	c.771G>A	p.Ala257=	synonymous_variant	8/8	5
HUS1	ENST00000458191.5	c.771G>A	p.Ala257=	synonymous_variant, NMD_transcript_variant	8/9	2

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69868 AN: 151892 Hom.: 16804 Cov.: 33

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.590

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.451

GnomAD3 exomes AF: 0.491 AC: 123259 AN: 251266 Hom.: 31054 AF XY: 0.485 AC XY: 65905 AN XY: 135812

Gnomad AFR exome AF: 0.311

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.549

Gnomad SAS exome AF: 0.381

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.512

Gnomad OTH exome AF: 0.485

GnomAD4 exome AF: 0.504 AC: 732621 AN: 1453964 Hom.: 187120 Cov.: 30 AF XY: 0.500 AC XY: 362118 AN XY: 723714

Gnomad4 AFR exome AF: 0.306

Gnomad4 AMR exome AF: 0.520

Gnomad4 ASJ exome AF: 0.454

Gnomad4 EAS exome AF: 0.526

Gnomad4 SAS exome AF: 0.382

Gnomad4 FIN exome AF: 0.583

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.487

GnomAD4 genome AF: 0.460 AC: 69884 AN: 152010 Hom.: 16801 Cov.: 33 AF XY: 0.465 AC XY: 34535 AN XY: 74294

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.498

Gnomad4 ASJ AF: 0.450

Gnomad4 EAS AF: 0.537

Gnomad4 SAS AF: 0.388

Gnomad4 FIN AF: 0.590

Gnomad4 NFE AF: 0.520

Gnomad4 OTH AF: 0.448

Alfa AF: 0.490 Hom.: 11621

Bravo AF: 0.446

Asia WGS AF: 0.477 AC: 1659 AN: 3478

EpiCase AF: 0.505

EpiControl AF: 0.495

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.30
Dann	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs1056663; hg19: chr7-48004962; COSMIC: COSV51840360; COSMIC: COSV51840360;