NM_000051.4:c.6347+31dupT

Variant names:

• chr11-108317539-A-AT
• rs58978479
• NM_000051.4:c.6347+31dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000051.4(ATM):​c.6347+31dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,225,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 24)
  • Exomes 𝑓: 0.027 (0 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.405
• Publications: 4 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 -8 ACMG points.

• BP6: Variant 11-108317539-A-AT is Benign according to our data. Variant chr11-108317539-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1209905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.6347+31dupT		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.6347+31dupT		intron	N/A	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-8469dupA		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.6347+18_6347+19insT		intron	N/A	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.6347+18_6347+19insT		intron	N/A	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*1411+18_*1411+19insT		intron	N/A	ENSP00000435747.2

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 142 AN: 125130 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000420

Gnomad ASJ AF: 0.00130

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.00253

Gnomad FIN AF: 0.00108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00179

GnomAD2 exomes AF: 0.0238 AC: 2430 AN: 101888 AF XY: 0.0240

Gnomad AFR exome AF: 0.00482

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.0299

Gnomad FIN exome AF: 0.0275

Gnomad NFE exome AF: 0.0249

Gnomad OTH exome AF: 0.0316

GnomAD4 exome AF: 0.0269 AC: 29564 AN: 1100414 Hom.: 0 Cov.: 0 AF XY: 0.0263 AC XY: 14443 AN XY: 548692

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0102 AC: 288 AN: 28270

American (AMR) AF: 0.0201 AC: 715 AN: 35490

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 516 AN: 20050

East Asian (EAS) AF: 0.0342 AC: 998 AN: 29170

South Asian (SAS) AF: 0.0218 AC: 1483 AN: 68006

European-Finnish (FIN) AF: 0.0294 AC: 1152 AN: 39118

Middle Eastern (MID) AF: 0.0178 AC: 84 AN: 4712

European-Non Finnish (NFE) AF: 0.0277 AC: 22992 AN: 829954

Other (OTH) AF: 0.0293 AC: 1336 AN: 45644

⚠️ 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 AF: 0.00113 AC: 142 AN: 125150 Hom.: 0 Cov.: 24 AF XY: 0.00120 AC XY: 72 AN XY: 59970

African (AFR) AF: 0.000489 AC: 17 AN: 34734

American (AMR) AF: 0.000419 AC: 5 AN: 11928

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 4 AN: 3068

East Asian (EAS) AF: 0.00118 AC: 5 AN: 4244

South Asian (SAS) AF: 0.00254 AC: 10 AN: 3932

European-Finnish (FIN) AF: 0.00108 AC: 7 AN: 6472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00157 AC: 91 AN: 58074

Other (OTH) AF: 0.00178 AC: 3 AN: 1684

Alfa AF: 0.0121 Hom.: 6

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Ataxia-telangiectasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs58978479; hg19: chr11-108188266; COSMIC: COSV53736193; COSMIC: COSV53736193;