rs2307252

Positions:

• chr7-47976845-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004507.4(HUS1):​c.358-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,552,762 control chromosomes in the GnomAD database, including 14,258 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2854 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11404 hom.)
• Consequence: HUS1 NM_004507.4 splice_region, intron
• Scores: Splicing: ADA: 0.00008641
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59

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]

HUS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUS1	NM_004507.4	c.358-8C>T		splice_region_variant, intron_variant		ENST00000258774.10	NP_004498.1
HUS1	NM_001363683.2	c.295-8C>T		splice_region_variant, intron_variant			NP_001350612.1
HUS1	NR_037917.2	n.512-8C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUS1	ENST00000258774.10	c.358-8C>T		splice_region_variant, intron_variant		1	NM_004507.4	ENSP00000258774.5

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25567 AN: 151540 Hom.: 2839 Cov.: 32

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.0878

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0992

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.143 AC: 35316 AN: 247628 Hom.: 3091 AF XY: 0.140 AC XY: 18799 AN XY: 134058

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.205

Gnomad SAS exome AF: 0.194

Gnomad FIN exome AF: 0.0892

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.117 AC: 164155 AN: 1401106 Hom.: 11404 Cov.: 23 AF XY: 0.118 AC XY: 82893 AN XY: 700424

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.0927

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.169 AC: 25638 AN: 151656 Hom.: 2854 Cov.: 32 AF XY: 0.168 AC XY: 12413 AN XY: 74066

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.0878

Gnomad4 NFE AF: 0.0992

Gnomad4 OTH AF: 0.146

Alfa AF: 0.110 Hom.: 1698

Bravo AF: 0.176

Asia WGS AF: 0.202 AC: 703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000086
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs2307252; hg19: chr7-48016442; COSMIC: COSV51839065; COSMIC: COSV51839065;