chr7-124853024-G-A

Variant names:

• chr7-124853024-G-A
• rs1554423983
• NM_015450.3:c.817C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_015450.3(POT1):​c.817C>T​(p.Arg273Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R273Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POT1 NM_015450.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.90
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-124853023-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475105.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	NM_015450.3	MANE Select	c.817C>T	p.Arg273Trp	missense	Exon 10 of 19	NP_056265.2
	POT1	NM_001042594.2		c.424C>T	p.Arg142Trp	missense	Exon 9 of 18	NP_001036059.1
	POT1	NR_003102.2		n.1260C>T		non_coding_transcript_exon	Exon 10 of 20

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	ENST00000357628.8	TSL:2 MANE Select	c.817C>T	p.Arg273Trp	missense	Exon 10 of 19	ENSP00000350249.3
	POT1	ENST00000607932.5	TSL:1	n.817C>T		non_coding_transcript_exon	Exon 6 of 14	ENSP00000476506.1
	POT1	ENST00000608057.5	TSL:1	n.817C>T		non_coding_transcript_exon	Exon 6 of 16	ENSP00000476371.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461126 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726886

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111470

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.62		Loss of disorder (P = 0.0134)
MVP		0.77
MPC		2.1
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.89
Mutation Taster		=21/79	disease causing

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: rs1554423983; hg19: chr7-124493078; COSMIC: COSV62929238;