8-73024898-A-G

Position:

• chr8-73024898-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017489.3(TERF1):​c.701A>G​(p.Asn234Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TERF1 NM_017489.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0500

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06607857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERF1	NM_017489.3	c.701A>G	p.Asn234Ser	missense_variant	5/10	ENST00000276603.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERF1	ENST00000276603.10	c.701A>G	p.Asn234Ser	missense_variant	5/10	1	NM_017489.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

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 04, 2023

The c.701A>G (p.N234S) alteration is located in exon 5 (coding exon 5) of the TERF1 gene. This alteration results from a A to G substitution at nucleotide position 701, causing the asparagine (N) at amino acid position 234 to be replaced by a serine (S). 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	0.064
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.3
DANN	Benign	0.74
DEOGEN2	Benign	0.25	T;.;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.66	N;N;N
REVEL	Benign	0.089
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.021	B;B;.
Vest4		0.14
MutPred		0.49		Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);.;
MVP		0.16
MPC		0.12
ClinPred		0.039	T
GERP RS		-1.4
Varity_R		0.053
gMVP		0.031

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr8-73937133;