rs4988065

Variant names:

• chr11-108309009-T-C
• rs4988065
• NM_000051.4:c.5762+1025T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):​c.5762+1025T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000851 in 1,528,390 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (30 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.210
• Publications: 0 publications found

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004275024).
• BP6: Variant 11-108309009-T-C is Benign according to our data. Variant chr11-108309009-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1193598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000506 (77/152216) while in subpopulation SAS AF = 0.016 (77/4826). AF 95% confidence interval is 0.0131. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.5762+1025T>C		intron_variant	Intron 38 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5762+1025T>C		intron_variant	Intron 38 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152098 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: 0.00

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00267 AC: 342 AN: 128302 AF XY: 0.00370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000250

GnomAD4 exome AF: 0.000889 AC: 1224 AN: 1376174 Hom.: 30 Cov.: 28 AF XY: 0.00133 AC XY: 905 AN XY: 679602

African (AFR) AF: 0.0000318 AC: 1 AN: 31426

American (AMR) AF: 0.0000280 AC: 1 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25122

East Asian (EAS) AF: 0.00 AC: 0 AN: 35610

South Asian (SAS) AF: 0.0148 AC: 1166 AN: 79048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33452

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5674

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1072480

Other (OTH) AF: 0.000902 AC: 52 AN: 57678

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000726 AC XY: 54 AN XY: 74420

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.00766 AC: 105

Asia WGS AF: 0.00665 AC: 23 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

C11orf65: BP4, BS1, BS2 -

Jul 26, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.0
DANN	Benign	0.66
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.21
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.037
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.083	T
Vest4		0.055
MutPred		0.16		Loss of glycosylation at T235 (P = 0.0364);
MVP		0.040
ClinPred		0.031	T
GERP RS		0.33
Mutation Taster		=100/0	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: rs4988065; hg19: chr11-108179736;