NM_000051.4:c.6437G>C

Variant names:

• chr11-108320043-G-C
• rs56815840
• NM_000051.4:c.6437G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000051.4(ATM):​c.6437G>C​(p.Ser2146Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,598,250 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2146G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:22 O:1
• Conservation: PhyloP100: 0.782
• Publications: 10 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 32 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045170784).
• BP6: Variant 11-108320043-G-C is Benign according to our data. Variant chr11-108320043-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133630.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00391 (595/152274) while in subpopulation AFR AF = 0.0125 (521/41546). AF 95% confidence interval is 0.0117. There are 8 homozygotes in GnomAd4. There are 265 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.6437G>C	p.Ser2146Thr	missense	Exon 44 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6437G>C	p.Ser2146Thr	missense	Exon 45 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-10972C>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.6437G>C	p.Ser2146Thr	missense	Exon 44 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6437G>C	p.Ser2146Thr	missense	Exon 45 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1501G>C		non_coding_transcript_exon	Exon 42 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 596 AN: 152156 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000959 AC: 239 AN: 249170 AF XY: 0.000608

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.000927

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000984

GnomAD4 exome AF: 0.000370 AC: 535 AN: 1445976 Hom.: 1 Cov.: 28 AF XY: 0.000287 AC XY: 207 AN XY: 720228

African (AFR) AF: 0.0128 AC: 424 AN: 33072

American (AMR) AF: 0.00141 AC: 63 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000547 AC: 6 AN: 1097730

Other (OTH) AF: 0.000684 AC: 41 AN: 59898

GnomAD4 genome AF: 0.00391 AC: 595 AN: 152274 Hom.: 8 Cov.: 32 AF XY: 0.00356 AC XY: 265 AN XY: 74456

African (AFR) AF: 0.0125 AC: 521 AN: 41546

American (AMR) AF: 0.00425 AC: 65 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000518 Hom.: 0

Bravo AF: 0.00494

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00131 AC: 159

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	5	not provided (5)
-	-	3	Ataxia-telangiectasia syndrome (3)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Familial cancer of breast (2)
-	1	-	Breast and/or ovarian cancer (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.74
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.10	N
PhyloP100		0.78
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.046
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.64
MPC		0.11
ClinPred		0.00059	T
GERP RS		2.4
Varity_R		0.077
gMVP		0.14
Mutation Taster		=98/2	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: rs56815840; hg19: chr11-108190770; COSMIC: COSV105845711;