7-47965525-G-T

Variant names:

• chr7-47965525-G-T
• rs2037483
• NM_004507.4:c.761-87C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004507.4(HUS1):​c.761-87C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 717,448 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HUS1 NM_004507.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUS1	NM_004507.4	c.761-87C>A		intron_variant	Intron 7 of 7	ENST00000258774.10	NP_004498.1
HUS1	NM_001363683.2	c.698-87C>A		intron_variant	Intron 7 of 7		NP_001350612.1
HUS1	NR_037917.2	n.915-87C>A		intron_variant	Intron 7 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUS1	ENST00000258774.10	c.761-87C>A		intron_variant	Intron 7 of 7	1	NM_004507.4	ENSP00000258774.5
HUS1	ENST00000432325.6	c.698-87C>A		intron_variant	Intron 7 of 7	5		ENSP00000416588.1
HUS1	ENST00000458191.5	n.698-87C>A		intron_variant	Intron 7 of 8	2		ENSP00000400727.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 1 AN: 717448 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 378446

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19214

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19422

East Asian (EAS) AF: 0.00 AC: 0 AN: 32746

South Asian (SAS) AF: 0.00 AC: 0 AN: 63962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4328

European-Non Finnish (NFE) AF: 0.00000215 AC: 1 AN: 464824

Other (OTH) AF: 0.00 AC: 0 AN: 35470

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.098
DANN	Benign	0.72
PhyloP100		-1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 4

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

Other links and lift over

dbSNP: rs2037483; hg19: chr7-48005122;