rs2307252

Variant names:

• chr7-47976845-G-A
• rs2307252
• NM_004507.4:c.358-8C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HUS1	NM_004507.4	c.358-8C>T		splice_region_variant, intron_variant	Intron 3 of 7	ENST00000258774.10	NP_004498.1
HUS1	NM_001363683.2	c.295-8C>T		splice_region_variant, intron_variant	Intron 3 of 7		NP_001350612.1
HUS1	NR_037917.2	n.512-8C>T		splice_region_variant, intron_variant	Intron 3 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUS1	ENST00000258774.10	c.358-8C>T		splice_region_variant, intron_variant	Intron 3 of 7	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

GnomAD2 exomes AF: 0.143 AC: 35316 AN: 247628 AF XY: 0.140

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 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

African (AFR) AF: 0.323 AC: 10373 AN: 32122

American (AMR) AF: 0.157 AC: 6960 AN: 44276

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2760 AN: 25676

East Asian (EAS) AF: 0.220 AC: 8656 AN: 39362

South Asian (SAS) AF: 0.198 AC: 16670 AN: 84258

European-Finnish (FIN) AF: 0.0927 AC: 4909 AN: 52978

Middle Eastern (MID) AF: 0.105 AC: 595 AN: 5644

European-Non Finnish (NFE) AF: 0.100 AC: 106047 AN: 1058360

Other (OTH) AF: 0.123 AC: 7185 AN: 58430

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

African (AFR) AF: 0.316 AC: 13026 AN: 41272

American (AMR) AF: 0.141 AC: 2152 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 390 AN: 3468

East Asian (EAS) AF: 0.215 AC: 1107 AN: 5140

South Asian (SAS) AF: 0.200 AC: 963 AN: 4808

European-Finnish (FIN) AF: 0.0878 AC: 920 AN: 10474

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0992 AC: 6739 AN: 67946

Other (OTH) AF: 0.146 AC: 307 AN: 2100

Alfa AF: 0.116 Hom.: 2360

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
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2307252; hg19: chr7-48016442; COSMIC: COSV51839065; COSMIC: COSV51839065;