NM_000051.4:c.8786+8A>C

Variant names:

• chr11-108353888-A-C
• rs4986839
• NM_000051.4:c.8786+8A>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.8786+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 1,604,136 control chromosomes in the GnomAD database, including 1,200 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (57 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1143 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002930
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 0.222
• Publications: 20 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 (BayesDel_noAF=-0.83).
• BP6: Variant 11-108353888-A-C is Benign according to our data. Variant chr11-108353888-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0246 (3740/152182) while in subpopulation NFE AF = 0.0377 (2565/68000). AF 95% confidence interval is 0.0365. There are 57 homozygotes in GnomAd4. There are 1715 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 57 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.8786+8A>C		splice_region intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.8786+8A>C		splice_region intron	N/A	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.640+32032T>G		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.8786+8A>C		splice_region intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.8786+8A>C		splice_region intron	N/A	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1196+1027T>G		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3742 AN: 152064 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.00776

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0262 AC: 6577 AN: 251450 AF XY: 0.0267

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.0173

Gnomad ASJ exome AF: 0.0829

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00845

Gnomad NFE exome AF: 0.0368

Gnomad OTH exome AF: 0.0329

GnomAD4 exome AF: 0.0356 AC: 51622 AN: 1451954 Hom.: 1143 Cov.: 29 AF XY: 0.0348 AC XY: 25143 AN XY: 723064

African (AFR) AF: 0.00635 AC: 211 AN: 33248

American (AMR) AF: 0.0179 AC: 802 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0829 AC: 2159 AN: 26058

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39628

South Asian (SAS) AF: 0.0161 AC: 1383 AN: 86062

European-Finnish (FIN) AF: 0.0110 AC: 587 AN: 53370

Middle Eastern (MID) AF: 0.0240 AC: 138 AN: 5758

European-Non Finnish (NFE) AF: 0.0402 AC: 44342 AN: 1103016

Other (OTH) AF: 0.0332 AC: 1996 AN: 60112

GnomAD4 genome AF: 0.0246 AC: 3740 AN: 152182 Hom.: 57 Cov.: 32 AF XY: 0.0230 AC XY: 1715 AN XY: 74418

African (AFR) AF: 0.00773 AC: 321 AN: 41514

American (AMR) AF: 0.0211 AC: 322 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0795 AC: 276 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4816

European-Finnish (FIN) AF: 0.00792 AC: 84 AN: 10600

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0377 AC: 2565 AN: 68000

Other (OTH) AF: 0.0307 AC: 65 AN: 2116

Alfa AF: 0.0357 Hom.: 208

Bravo AF: 0.0261

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Ataxia-telangiectasia syndrome (6)
-	-	6	Hereditary cancer-predisposing syndrome (6)
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	2	Familial cancer of breast (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.79
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.16		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: rs4986839; hg19: chr11-108224615;