rs1313494164

Variant names:

• chr3-48446873-A-C
• rs1313494164
• NM_130384.3:c.28A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_130384.3(ATRIP):​c.28A>C​(p.Lys10Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000008 in 1,250,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: ATRIP NM_130384.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.427
• 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-TREX1 (HGNC:):

CCDC51 (HGNC:25714): (coiled-coil domain containing 51) Enables mitochondrial ATP-gated potassium channel activity. Involved in potassium ion transmembrane transport. Is integral component of mitochondrial inner membrane. Part of mitochondrial ATP-gated potassium channel complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07586485).

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.28A>C	p.Lys10Gln	missense	Exon 1 of 13	NP_569055.1	Q8WXE1-1
	ATRIP	NM_032166.4		c.28A>C	p.Lys10Gln	missense	Exon 1 of 12	NP_115542.2
	ATRIP	NM_001271022.2		c.-218+74A>C		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.28A>C	p.Lys10Gln	missense	Exon 1 of 13	ENSP00000323099.3	Q8WXE1-1
	ATRIP	ENST00000346691.9	TSL:1	c.28A>C	p.Lys10Gln	missense	Exon 1 of 12	ENSP00000302338.5	Q8WXE1-2
	ATRIP	ENST00000949799.1		c.28A>C	p.Lys10Gln	missense	Exon 1 of 14	ENSP00000619858.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.00e-7 AC: 1 AN: 1250354 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 611616

⚠️ 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: 25188

American (AMR) AF: 0.00 AC: 0 AN: 17576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16726

East Asian (EAS) AF: 0.00 AC: 0 AN: 30910

South Asian (SAS) AF: 0.00 AC: 0 AN: 49024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3580

European-Non Finnish (NFE) AF: 9.87e-7 AC: 1 AN: 1012706

Other (OTH) AF: 0.00 AC: 0 AN: 50416

⚠️ 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

Bravo AF: 0.00000756

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	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.43
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.019
Sift	Benign	0.054	T
Sift4G	Uncertain	0.057	T
Polyphen		0.13	B
Vest4		0.19
MutPred		0.24		Loss of methylation at K10 (P = 0.002)
MVP		0.25
MPC		0.29
ClinPred		0.16	T
GERP RS		-0.018
PromoterAI		-0.024	Neutral
Varity_R		0.091
gMVP		0.20
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1313494164; hg19: chr3-48488277;