16-75647801-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018975.4(TERF2IP):c.-82G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,591,968 control chromosomes in the GnomAD database, including 641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (111 hom., cov: 33)
  • Exomes 𝑓: 0.020 (530 hom.)
• Consequence: TERF2IP NM_018975.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.666

Genes affected

TERF2IP (HGNC:19246): (TERF2 interacting protein) Enables G-rich strand telomeric DNA binding activity and phosphatase binding activity. Involved in several processes, including positive regulation of NIK/NF-kappaB signaling; regulation of nucleobase-containing compound metabolic process; and regulation of protein modification process. Located in chromosome, telomeric region; cytosol; and nuclear body. Part of shelterin complex. [provided by Alliance of Genome Resources, Apr 2022]

KARS1 (HGNC:6215): (lysyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-75647801-G-T is Benign according to our data. Variant chr16-75647801-G-T is described in ClinVar as [Benign]. Clinvar id is 1252803.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-75647801-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERF2IP	NM_018975.4	c.-82G>T		5_prime_UTR_variant	1/3	ENST00000300086.5
TERF2IP	XM_047434216.1	c.-82G>T		5_prime_UTR_variant	1/2
TERF2IP	NR_144545.2	n.29G>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERF2IP	ENST00000300086.5	c.-82G>T		5_prime_UTR_variant	1/3	1	NM_018975.4	P1
KARS1	ENST00000566560.5	n.176+667C>A		intron_variant, non_coding_transcript_variant		1
TERF2IP	ENST00000653858.1	c.-82G>T		5_prime_UTR_variant	1/4

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4733 AN: 152226 Hom.: 111 Cov.: 33

Gnomad AFR AF: 0.0633

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0288

Gnomad SAS AF: 0.0577

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0306

GnomAD4 exome AF: 0.0205 AC: 29496 AN: 1439624 Hom.: 530 Cov.: 28 AF XY: 0.0219 AC XY: 15668 AN XY: 715856

Gnomad4 AFR exome AF: 0.0674

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.0315

Gnomad4 EAS exome AF: 0.0255

Gnomad4 SAS exome AF: 0.0656

Gnomad4 FIN exome AF: 0.00601

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0253

GnomAD4 genome AF: 0.0311 AC: 4736 AN: 152344 Hom.: 111 Cov.: 33 AF XY: 0.0309 AC XY: 2303 AN XY: 74494

Gnomad4 AFR AF: 0.0633

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.0288

Gnomad4 SAS AF: 0.0571

Gnomad4 FIN AF: 0.00593

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.0302

Alfa AF: 0.0199 Hom.: 45

Bravo AF: 0.0329

Asia WGS AF: 0.0640 AC: 220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.4
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs920037; hg19: chr16-75681699;