8-73013924-G-C

Position:

• chr8-73013924-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017489.3(TERF1):​c.349G>C​(p.Ala117Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,812 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TERF1 NM_017489.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.505

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERF1	NM_017489.3	c.349G>C	p.Ala117Pro	missense_variant	2/10	ENST00000276603.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERF1	ENST00000276603.10	c.349G>C	p.Ala117Pro	missense_variant	2/10	1	NM_017489.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458812 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725706

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.349G>C (p.A117P) alteration is located in exon 2 (coding exon 2) of the TERF1 gene. This alteration results from a G to C substitution at nucleotide position 349, causing the alanine (A) at amino acid position 117 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;T
Eigen	Benign	0.026
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	0.56	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.065	T;T;T
Sift4G	Benign	0.10	T;T;D
Polyphen		0.99	D;D;.
Vest4		0.20
MutPred		0.82		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);.;
MVP		0.49
MPC		0.64
ClinPred		0.66	D
GERP RS		-0.31
Varity_R		0.52
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-73926159;