rs55834252

chr8-73024967-T-Achr8-73024967-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017489.3(TERF1):c.770T>A(p.Met257Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TERF1 NM_017489.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94

Genes affected

TERF1 (HGNC:11728): (telomeric repeat binding factor 1) This gene encodes a telomere specific protein which is a component of the telomere nucleoprotein complex. This protein is present at telomeres throughout the cell cycle and functions as an inhibitor of telomerase, acting in cis to limit the elongation of individual chromosome ends. The protein structure contains a C-terminal Myb motif, a dimerization domain near its N-terminus and an acidic N-terminus. Multiple transcripts of this gene are alternatively spliced products. [provided by RefSeq, Aug 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERF1	NM_017489.3	c.770T>A	p.Met257Lys	missense_variant	5/10	ENST00000276603.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERF1	ENST00000276603.10	c.770T>A	p.Met257Lys	missense_variant	5/10	1	NM_017489.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000445 AC: 1 AN: 224650 Hom.: 0 AF XY: 0.00000813 AC XY: 1 AN XY: 123066

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000375

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399444 Hom.: 0 Cov.: 26 AF XY: 0.00000143 AC XY: 1 AN XY: 698570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.81	P;P;.
Vest4		0.78
MutPred		0.79		Gain of disorder (P = 0.0174);Gain of disorder (P = 0.0174);.;
MVP		0.62
MPC		0.70
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs55834252; hg19: chr8-73937202;