rs1800060

Variant names:

• chr11-108317409-G-A
• rs1800060
• NM_000051.4:c.6235G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108317409-G-A
• chr11-108317409-G-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.6235G>A​(p.Val2079Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,611,760 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2079F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0059 (9 hom., cov: 28)
  • Exomes 𝑓: 0.0013 (7 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25 O:1
• Conservation: PhyloP100: -0.0380
• Publications: 25 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=0.008029282).
• BP6: Variant 11-108317409-G-A is Benign according to our data. Variant chr11-108317409-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00592 (897/151400) while in subpopulation AFR AF = 0.0174 (718/41218). AF 95% confidence interval is 0.0164. There are 9 homozygotes in GnomAd4. There are 414 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. 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
	ATM	NM_000051.4	MANE Select	c.6235G>A	p.Val2079Ile	missense	Exon 43 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6235G>A	p.Val2079Ile	missense	Exon 44 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-8338C>T		intron	N/A	NP_001317297.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.6235G>A	p.Val2079Ile	missense	Exon 43 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6235G>A	p.Val2079Ile	missense	Exon 44 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1299G>A		non_coding_transcript_exon	Exon 41 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 898 AN: 151284 Hom.: 9 Cov.: 28

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00508

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.0000961

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.00530

GnomAD2 exomes AF: 0.00252 AC: 634 AN: 251386 AF XY: 0.00202

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000748

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00128 AC: 1864 AN: 1460360 Hom.: 7 Cov.: 30 AF XY: 0.00120 AC XY: 875 AN XY: 726554

African (AFR) AF: 0.0184 AC: 616 AN: 33416

American (AMR) AF: 0.00226 AC: 101 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 372 AN: 26090

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39610

South Asian (SAS) AF: 0.00118 AC: 102 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5764

European-Non Finnish (NFE) AF: 0.000462 AC: 513 AN: 1111022

Other (OTH) AF: 0.00244 AC: 147 AN: 60290

GnomAD4 genome AF: 0.00592 AC: 897 AN: 151400 Hom.: 9 Cov.: 28 AF XY: 0.00560 AC XY: 414 AN XY: 73910

African (AFR) AF: 0.0174 AC: 718 AN: 41218

American (AMR) AF: 0.00507 AC: 77 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3464

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5118

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4810

European-Finnish (FIN) AF: 0.0000961 AC: 1 AN: 10406

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

European-Non Finnish (NFE) AF: 0.000589 AC: 40 AN: 67904

Other (OTH) AF: 0.00525 AC: 11 AN: 2096

Alfa AF: 0.00367 Hom.: 7

Bravo AF: 0.00731

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00257 AC: 312

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	6	Ataxia-telangiectasia syndrome (6)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	2	Familial cancer of breast (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0050
DANN	Benign	0.62
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.038
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.078
Sift	Benign	0.40	T
Sift4G	Benign	0.50	T
Polyphen		0.0020	B
Vest4		0.10
MVP		0.44
MPC		0.099
ClinPred		0.0056	T
GERP RS		-12
Varity_R		0.038
gMVP		0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1800060; hg19: chr11-108188136; COSMIC: COSV53744931; COSMIC: COSV53744931;