rs11556639

Positions:

• chr16-75647913-C-G
• chr16-75647913-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018975.4(TERF2IP):​c.31C>G​(p.Pro11Ala) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TERF2IP NM_018975.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26063317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERF2IP	NM_018975.4	c.31C>G	p.Pro11Ala	missense_variant	1/3	ENST00000300086.5	NP_061848.2
TERF2IP	XM_047434216.1	c.31C>G	p.Pro11Ala	missense_variant	1/2		XP_047290172.1
TERF2IP	NR_144545.2	n.141C>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERF2IP	ENST00000300086.5	c.31C>G	p.Pro11Ala	missense_variant	1/3	1	NM_018975.4	ENSP00000300086.4
KARS1	ENST00000566560.5	n.176+555G>C		intron_variant		1
TERF2IP	ENST00000653858.1	c.31C>G	p.Pro11Ala	missense_variant	1/4			ENSP00000499565.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.096
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.090	T
Polyphen		0.80	P
Vest4		0.26
MutPred		0.46		Loss of methylation at K9 (P = 0.0656);
MVP		0.77
MPC		1.5
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.28
gMVP		0.42

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: rs11556639; hg19: chr16-75681811;