3-48446930-C-T

Variant names:

• chr3-48446930-C-T
• rs530772573
• NM_130384.3:c.85C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_130384.3(ATRIP):​c.85C>T​(p.Pro29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P29L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATRIP NM_130384.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30259192).

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.85C>T	p.Pro29Ser	missense	Exon 1 of 13	NP_569055.1	Q8WXE1-1
	ATRIP	NM_032166.4		c.85C>T	p.Pro29Ser	missense	Exon 1 of 12	NP_115542.2
	ATRIP	NM_001271022.2		c.-218+131C>T		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.85C>T	p.Pro29Ser	missense	Exon 1 of 13	ENSP00000323099.3	Q8WXE1-1
	ATRIP	ENST00000346691.9	TSL:1	c.85C>T	p.Pro29Ser	missense	Exon 1 of 12	ENSP00000302338.5	Q8WXE1-2
	ATRIP	ENST00000949799.1		c.85C>T	p.Pro29Ser	missense	Exon 1 of 14	ENSP00000619858.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1302080 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 641952

African (AFR) AF: 0.00 AC: 0 AN: 26674

American (AMR) AF: 0.00 AC: 0 AN: 20326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20556

East Asian (EAS) AF: 0.00 AC: 0 AN: 30214

South Asian (SAS) AF: 0.00 AC: 0 AN: 64338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1035550

Other (OTH) AF: 0.00 AC: 0 AN: 53076

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74444

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.044
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.24		Gain of phosphorylation at P29 (P = 0.0108)
MVP		0.65
MPC		0.93
ClinPred		0.99	D
GERP RS		4.6
PromoterAI		-0.044	Neutral
Varity_R		0.47
gMVP		0.46
Mutation Taster		=87/13	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: rs530772573; hg19: chr3-48488334;