NM_001136505.2:c.998A>G

Variant names:

• chr16-66775231-T-C
• rs1167140633
• NM_001136505.2:c.998A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001136505.2(TERB1):​c.998A>G​(p.Tyr333Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,398,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: TERB1 NM_001136505.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

Genes affected

TERB1 (HGNC:26675): (telomere repeat binding bouquet formation protein 1) Predicted to be involved in homologous chromosome pairing at meiosis and meiotic attachment of telomere to nuclear envelope. Predicted to be located in chromosome, telomeric region and nuclear inner membrane. Predicted to colocalize with shelterin complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.7865 (below the threshold of 3.09). Trascript score misZ: 1.7409 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.096254826).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136505.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERB1	NM_001136505.2	MANE Select	c.998A>G	p.Tyr333Cys	missense	Exon 12 of 19	NP_001129977.1	Q8NA31-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TERB1	ENST00000433154.6	TSL:5 MANE Select	c.998A>G	p.Tyr333Cys	missense	Exon 12 of 19	ENSP00000463762.1	Q8NA31-1
	TERB1	ENST00000558713.6	TSL:5	c.998A>G	p.Tyr333Cys	missense	Exon 11 of 18	ENSP00000462883.1	Q8NA31-1
	TERB1	ENST00000673664.1		c.965A>G	p.Tyr322Cys	missense	Exon 12 of 12	ENSP00000500999.1	A0A669KAY0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000195 AC: 3 AN: 153948 AF XY: 0.0000245

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000812

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000501 AC: 7 AN: 1398486 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 689830

African (AFR) AF: 0.00 AC: 0 AN: 31576

American (AMR) AF: 0.000112 AC: 4 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35710

South Asian (SAS) AF: 0.00 AC: 0 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078212

Other (OTH) AF: 0.00 AC: 0 AN: 57970

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Uncertain	0.54	T
REVEL	Benign	0.082
Sift4G	Benign	0.14	T
Polyphen		0.017	B
Vest4		0.24
MutPred		0.26		Loss of phosphorylation at Y333 (P = 0.0523)
MVP		0.22
ClinPred		0.078	T
GERP RS		2.9
Varity_R		0.097
gMVP		0.28

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

Other links and lift over

dbSNP: rs1167140633; hg19: chr16-66809134;