NM_015450.3:c.197A>G

Variant names:

• chr7-124870969-T-C
• rs776085350
• NM_015450.3:c.197A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_015450.3(POT1):​c.197A>G​(p.Tyr66Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: POT1 NM_015450.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.64
• Publications: 0 publications found

Genes affected

POT1 (HGNC:17284): (protection of telomeres 1) This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

POT1 Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• tumor predisposition syndrome 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• glioma susceptibility 9

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• thyroid gland carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• cerebroretinal microangiopathy with calcifications and cysts 3

  Inheritance: AR Classification: LIMITED Submitted by: G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17467642).
• BP6: Variant 7-124870969-T-C is Benign according to our data. Variant chr7-124870969-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475069.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015450.3. 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
	POT1	NM_015450.3	MANE Select	c.197A>G	p.Tyr66Cys	missense	Exon 7 of 19	NP_056265.2	Q9NUX5-1
	POT1	NM_001042594.2		c.-138-7329A>G		intron	N/A	NP_001036059.1	A8MTK3
	POT1	NR_003102.2		n.640A>G		non_coding_transcript_exon	Exon 7 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	ENST00000357628.8	TSL:2 MANE Select	c.197A>G	p.Tyr66Cys	missense	Exon 7 of 19	ENSP00000350249.3	Q9NUX5-1
	POT1	ENST00000607932.5	TSL:1	n.197A>G		non_coding_transcript_exon	Exon 3 of 14	ENSP00000476506.1	Q5MJ34
	POT1	ENST00000608057.5	TSL:1	n.197A>G		non_coding_transcript_exon	Exon 3 of 16	ENSP00000476371.1	Q5MJ35

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249700 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458460 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725668

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.0000449 AC: 2 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109862

Other (OTH) AF: 0.0000166 AC: 1 AN: 60214

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Tumor predisposition syndrome 3 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.16	T
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.33
MutPred		0.53		Loss of catalytic residue at P70 (P = 0.0684)
MVP		0.39
MPC		1.1
ClinPred		0.17	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.75
Mutation Taster		=61/39	polymorphism

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: rs776085350; hg19: chr7-124511023;