3-48446905-C-A

Variant names:

• chr3-48446905-C-A
• rs1481032933
• NM_130384.3:c.60C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_130384.3(ATRIP):​c.60C>A​(p.Pro20Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000808 in 1,237,256 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. Synonymous variant affecting the same amino acid position (i.e. P20P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: ATRIP NM_130384.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 0 publications found

Genes affected

ATRIP (HGNC:33499): (ATR interacting protein) This gene encodes an essential component of the DNA damage checkpoint. The encoded protein binds to single-stranded DNA coated with replication protein A. The protein also interacts with the ataxia telangiectasia and Rad3 related protein kinase, resulting in its accumulation at intranuclear foci induced by DNA damage. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

ATRIP Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ATRIP-TREX1 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRIP	NM_130384.3	MANE Select	c.60C>A	p.Pro20Pro	synonymous	Exon 1 of 13	NP_569055.1	Q8WXE1-1
	ATRIP	NM_032166.4		c.60C>A	p.Pro20Pro	synonymous	Exon 1 of 12	NP_115542.2
	ATRIP	NM_001271022.2		c.-218+106C>A		intron	N/A	NP_001257951.1	Q8WXE1-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRIP	ENST00000320211.10	TSL:1 MANE Select	c.60C>A	p.Pro20Pro	synonymous	Exon 1 of 13	ENSP00000323099.3	Q8WXE1-1
	ATRIP	ENST00000346691.9	TSL:1	c.60C>A	p.Pro20Pro	synonymous	Exon 1 of 12	ENSP00000302338.5	Q8WXE1-2
	ATRIP	ENST00000949799.1		c.60C>A	p.Pro20Pro	synonymous	Exon 1 of 14	ENSP00000619858.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.08e-7 AC: 1 AN: 1237256 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 603720

⚠️ 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: 25064

American (AMR) AF: 0.0000804 AC: 1 AN: 12444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16698

East Asian (EAS) AF: 0.00 AC: 0 AN: 29858

South Asian (SAS) AF: 0.00 AC: 0 AN: 50130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3984

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1006056

Other (OTH) AF: 0.00 AC: 0 AN: 50184

⚠️ 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.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.3
DANN	Benign	0.85
PhyloP100		-1.2
PromoterAI		0.15	Neutral
Mutation Taster		=100/0	polymorphism

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: rs1481032933; hg19: chr3-48488309; COSMIC: COSV57177502; COSMIC: COSV57177502;