chr7-47965365-C-T

Variant names:

• chr7-47965365-C-T
• rs1056663
• NM_004507.4:c.834G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004507.4(HUS1):​c.834G>A​(p.Ala278Ala) 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
• Publications: 29 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 -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 rank	MANE	Protein	UniProt
HUS1	NM_004507.4	c.834G>A	p.Ala278Ala	synonymous_variant	Exon 8 of 8	ENST00000258774.10	NP_004498.1
HUS1	NM_001363683.2	c.771G>A	p.Ala257Ala	synonymous_variant	Exon 8 of 8		NP_001350612.1
HUS1	NR_037917.2	n.988G>A		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUS1	ENST00000258774.10	c.834G>A	p.Ala278Ala	synonymous_variant	Exon 8 of 8	1	NM_004507.4	ENSP00000258774.5
HUS1	ENST00000432325.6	c.771G>A	p.Ala257Ala	synonymous_variant	Exon 8 of 8	5		ENSP00000416588.1
HUS1	ENST00000458191.5	n.771G>A		non_coding_transcript_exon_variant	Exon 8 of 9	2		ENSP00000400727.1

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

GnomAD2 exomes AF: 0.491 AC: 123259 AN: 251266 AF XY: 0.485

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 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

African (AFR) AF: 0.306 AC: 10192 AN: 33350

American (AMR) AF: 0.520 AC: 23235 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 11847 AN: 26084

East Asian (EAS) AF: 0.526 AC: 20858 AN: 39636

South Asian (SAS) AF: 0.382 AC: 32902 AN: 86132

European-Finnish (FIN) AF: 0.583 AC: 31082 AN: 53282

Middle Eastern (MID) AF: 0.401 AC: 2306 AN: 5744

European-Non Finnish (NFE) AF: 0.517 AC: 570902 AN: 1104916

Other (OTH) AF: 0.487 AC: 29297 AN: 60128

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

African (AFR) AF: 0.314 AC: 13031 AN: 41446

American (AMR) AF: 0.498 AC: 7604 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1560 AN: 3466

East Asian (EAS) AF: 0.537 AC: 2764 AN: 5150

South Asian (SAS) AF: 0.388 AC: 1867 AN: 4818

European-Finnish (FIN) AF: 0.590 AC: 6244 AN: 10582

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35321 AN: 67948

Other (OTH) AF: 0.448 AC: 946 AN: 2110

Alfa AF: 0.491 Hom.: 38110

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
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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