ENST00000527805.6:n.*4471C>T

Variant names:

• chr11-108365744-C-T
• rs3092834
• ENST00000527805.6:n.*4471C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000527805.6(ATM):​n.*4471C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 552,478 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0058 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: ATM ENST00000527805.6 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.63
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-108365744-C-T is Benign according to our data. Variant chr11-108365744-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 302258.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00585 (888/151912) while in subpopulation AFR AF = 0.0174 (720/41440). AF 95% confidence interval is 0.0163. There are 8 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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: ENST00000527805.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.*236C>T		3_prime_UTR	Exon 63 of 63	NP_000042.3
	ATM	NM_001351834.2		c.*236C>T		3_prime_UTR	Exon 64 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.640+20176G>A		intron	N/A	NP_001317297.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000527805.6	TSL:1	n.*4471C>T		non_coding_transcript_exon	Exon 61 of 61	ENSP00000435747.2
	ATM	ENST00000675843.1	MANE Select	c.*236C>T		3_prime_UTR	Exon 63 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.*236C>T		3_prime_UTR	Exon 64 of 64	ENSP00000388058.2

Frequencies

GnomAD3 genomes AF: 0.00586 AC: 889 AN: 151794 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00493

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000833

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00576

GnomAD4 exome AF: 0.00159 AC: 635 AN: 400566 Hom.: 1 Cov.: 5 AF XY: 0.00148 AC XY: 311 AN XY: 210766

African (AFR) AF: 0.0161 AC: 183 AN: 11384

American (AMR) AF: 0.00265 AC: 41 AN: 15468

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 157 AN: 11582

East Asian (EAS) AF: 0.00 AC: 0 AN: 24072

South Asian (SAS) AF: 0.00166 AC: 72 AN: 43314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17746

Middle Eastern (MID) AF: 0.00308 AC: 5 AN: 1622

European-Non Finnish (NFE) AF: 0.000458 AC: 116 AN: 253186

Other (OTH) AF: 0.00275 AC: 61 AN: 22192

GnomAD4 genome AF: 0.00585 AC: 888 AN: 151912 Hom.: 8 Cov.: 31 AF XY: 0.00547 AC XY: 406 AN XY: 74272

African (AFR) AF: 0.0174 AC: 720 AN: 41440

American (AMR) AF: 0.00492 AC: 75 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000625 AC: 3 AN: 4798

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10550

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

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 67946

Other (OTH) AF: 0.00570 AC: 12 AN: 2106

Alfa AF: 0.00520 Hom.: 0

Bravo AF: 0.00716

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.65
PhyloP100		-2.6
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: rs3092834; hg19: chr11-108236471;