rs56360226

Variant names:

• chr11-108365221-G-A
• rs56360226
• NM_000051.4:c.8987+3G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108365221-G-A
• chr11-108365221-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000051.4(ATM):​c.8987+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001652
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 1.40
• Publications: 3 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

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 11-108365221-G-A is Benign according to our data. Variant chr11-108365221-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 184495.

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.8987+3G>A		splice_region intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.8987+3G>A		splice_region intron	N/A	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.640+20699C>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.8987+3G>A		splice_region intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.8987+3G>A		splice_region intron	N/A	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*2-9112C>T		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000111 AC: 28 AN: 251390 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000267 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	Ataxia-telangiectasia syndrome (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	ATM-related disorder (1)
-	-	1	Familial cancer of breast (1)
-	1	-	Familial ovarian cancer (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.73
PhyloP100		1.4
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0040
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: rs56360226; hg19: chr11-108235948;