16-75647858-C-A

Position:

• chr16-75647858-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018975.4(TERF2IP):​c.-25C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,601,202 control chromosomes in the GnomAD database, including 1,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (163 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1453 hom.)
• Consequence: TERF2IP NM_018975.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.09

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-75647858-C-A is Benign according to our data. Variant chr16-75647858-C-A is described in ClinVar as [Benign]. Clinvar id is 1249847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75647858-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERF2IP	NM_018975.4	c.-25C>A		5_prime_UTR_variant	1/3	ENST00000300086.5	NP_061848.2
TERF2IP	XM_047434216.1	c.-25C>A		5_prime_UTR_variant	1/2		XP_047290172.1
TERF2IP	NR_144545.2	n.86C>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERF2IP	ENST00000300086.5	c.-25C>A		5_prime_UTR_variant	1/3	1	NM_018975.4	ENSP00000300086	P1
KARS1	ENST00000566560.5	n.176+610G>T		intron_variant, non_coding_transcript_variant		1
TERF2IP	ENST00000653858.1	c.-25C>A		5_prime_UTR_variant	1/4			ENSP00000499565

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6578 AN: 152186 Hom.: 162 Cov.: 32

Gnomad AFR AF: 0.0524

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.0495

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0339

GnomAD3 exomes AF: 0.0395 AC: 9644 AN: 244046 Hom.: 237 AF XY: 0.0403 AC XY: 5322 AN XY: 132218

Gnomad AFR exome AF: 0.0561

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0389

Gnomad EAS exome AF: 0.0128

Gnomad SAS exome AF: 0.0491

Gnomad FIN exome AF: 0.0661

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0381

GnomAD4 exome AF: 0.0419 AC: 60736 AN: 1448898 Hom.: 1453 Cov.: 31 AF XY: 0.0420 AC XY: 30199 AN XY: 718934

Gnomad4 AFR exome AF: 0.0558

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.0416

Gnomad4 EAS exome AF: 0.0127

Gnomad4 SAS exome AF: 0.0481

Gnomad4 FIN exome AF: 0.0682

Gnomad4 NFE exome AF: 0.0417

Gnomad4 OTH exome AF: 0.0447

GnomAD4 genome AF: 0.0432 AC: 6581 AN: 152304 Hom.: 163 Cov.: 32 AF XY: 0.0429 AC XY: 3191 AN XY: 74468

Gnomad4 AFR AF: 0.0523

Gnomad4 AMR AF: 0.0216

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.0137

Gnomad4 SAS AF: 0.0497

Gnomad4 FIN AF: 0.0651

Gnomad4 NFE AF: 0.0416

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0332 Hom.: 34

Bravo AF: 0.0410

Asia WGS AF: 0.0400 AC: 140 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.54
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs2233810; hg19: chr16-75681756;