rs4987114

Variant names:

• chr11-108368921-T-C
• rs4987114
• NM_000051.4:c.*3413T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000051.4(ATM):​c.*3413T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 194,454 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (8 hom.)
• Consequence: ATM NM_000051.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.64
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-108368921-T-C is Benign according to our data. Variant chr11-108368921-T-C is described in ClinVar as Benign. ClinVar VariationId is 877112.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00169 (258/152334) while in subpopulation EAS AF = 0.0449 (233/5194). AF 95% confidence interval is 0.0401. There are 8 homozygotes in GnomAd4. There are 147 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.*3413T>C		3_prime_UTR_variant	Exon 63 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.*3413T>C		3_prime_UTR_variant	Exon 63 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 258 AN: 152216 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0448

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00864 AC: 364 AN: 42120 Hom.: 8 Cov.: 0 AF XY: 0.00835 AC XY: 164 AN XY: 19642

African (AFR) AF: 0.00 AC: 0 AN: 1790

American (AMR) AF: 0.00 AC: 0 AN: 1112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2706

East Asian (EAS) AF: 0.0506 AC: 356 AN: 7032

South Asian (SAS) AF: 0.00 AC: 0 AN: 364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24

Middle Eastern (MID) AF: 0.00400 AC: 1 AN: 250

European-Non Finnish (NFE) AF: 0.000158 AC: 4 AN: 25362

Other (OTH) AF: 0.000862 AC: 3 AN: 3480

GnomAD4 genome AF: 0.00169 AC: 258 AN: 152334 Hom.: 8 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.000131 AC: 2 AN: 15294

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

East Asian (EAS) AF: 0.0449 AC: 233 AN: 5194

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

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

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000239 Hom.: 13

Bravo AF: 0.00193

Asia WGS AF: 0.0160 AC: 54 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ataxia-telangiectasia syndrome Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.1
DANN	Benign	0.68
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: rs4987114; hg19: chr11-108239648;