chr3-48464819-C-A

Variant names:

• chr3-48464819-C-A
• rs3135936
• NM_130384.3:c.2056-12C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130384.3(ATRIP):​c.2056-12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,604,518 control chromosomes in the GnomAD database, including 549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (276 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (273 hom.)
• Consequence: ATRIP NM_130384.3 intron
• Scores: Splicing: ADA: 0.00004487
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.214
• Publications: 1 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

ATRIP-TREX1 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-48464819-C-A is Benign according to our data. Variant chr3-48464819-C-A is described in ClinVar as Benign. ClinVar VariationId is 1276028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

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.2056-12C>A		intron	N/A	NP_569055.1
	ATRIP	NM_032166.4		c.1975-12C>A		intron	N/A	NP_115542.2
	ATRIP	NM_001271023.2		c.1777-12C>A		intron	N/A	NP_001257952.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRIP	ENST00000320211.10	TSL:1 MANE Select	c.2056-12C>A		intron	N/A	ENSP00000323099.3
	ATRIP	ENST00000346691.9	TSL:1	c.1975-12C>A		intron	N/A	ENSP00000302338.5
	ATRIP	ENST00000412052.4	TSL:1	c.1777-12C>A		intron	N/A	ENSP00000400930.1

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5225 AN: 152108 Hom.: 268 Cov.: 33

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0101 AC: 2504 AN: 247566 AF XY: 0.00765

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.00802

Gnomad ASJ exome AF: 0.0192

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.00811

GnomAD4 exome AF: 0.00459 AC: 6664 AN: 1452292 Hom.: 273 Cov.: 35 AF XY: 0.00421 AC XY: 3034 AN XY: 720554

African (AFR) AF: 0.122 AC: 4047 AN: 33308

American (AMR) AF: 0.00890 AC: 396 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 438 AN: 25788

East Asian (EAS) AF: 0.00 AC: 0 AN: 39406

South Asian (SAS) AF: 0.000291 AC: 25 AN: 85808

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53000

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5738

European-Non Finnish (NFE) AF: 0.000925 AC: 1022 AN: 1104840

Other (OTH) AF: 0.0108 AC: 646 AN: 59894

GnomAD4 genome AF: 0.0346 AC: 5267 AN: 152226 Hom.: 276 Cov.: 33 AF XY: 0.0343 AC XY: 2556 AN XY: 74432

African (AFR) AF: 0.116 AC: 4801 AN: 41530

American (AMR) AF: 0.0148 AC: 227 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 68002

Other (OTH) AF: 0.0265 AC: 56 AN: 2110

Alfa AF: 0.0196 Hom.: 29

Bravo AF: 0.0396

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.76
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.050		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: rs3135936; hg19: chr3-48506218;