rs537377921

Variant names:

• chr7-124829254-C-G
• rs537377921
• NM_015450.3:c.1594G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-124829254-C-G
• chr7-124829254-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_015450.3(POT1):​c.1594G>C​(p.Ala532Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000418 in 1,435,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. A532T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: POT1 NM_015450.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.57
• Publications: 13 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: Uncertain_significance. The variant received 4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1594G>C	p.Ala532Pro	missense splice_region	Exon 16 of 19	NP_056265.2	Q9NUX5-1
	POT1	NM_001042594.2		c.1201G>C	p.Ala401Pro	missense splice_region	Exon 15 of 18	NP_001036059.1	A8MTK3
	POT1	NR_003102.2		n.2157G>C		splice_region non_coding_transcript_exon	Exon 17 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	ENST00000357628.8	TSL:2 MANE Select	c.1594G>C	p.Ala532Pro	missense splice_region	Exon 16 of 19	ENSP00000350249.3	Q9NUX5-1
	POT1	ENST00000608057.5	TSL:1	n.*691G>C		splice_region non_coding_transcript_exon	Exon 13 of 16	ENSP00000476371.1	Q5MJ35
	POT1	ENST00000608057.5	TSL:1	n.*691G>C		3_prime_UTR	Exon 13 of 16	ENSP00000476371.1	Q5MJ35

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000418 AC: 6 AN: 1435734 Hom.: 0 Cov.: 29 AF XY: 0.00000280 AC XY: 2 AN XY: 715440

African (AFR) AF: 0.00 AC: 0 AN: 32752

American (AMR) AF: 0.00 AC: 0 AN: 44062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.00 AC: 0 AN: 84750

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090218

Other (OTH) AF: 0.0000168 AC: 1 AN: 59470

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

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	0.64
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.58
Sift	Benign	0.030	D
Sift4G	Benign	0.074	T
Polyphen		0.67	P
Vest4		0.30
MutPred		0.40		Loss of stability (P = 0.0611)
MVP		0.32
MPC		0.25
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.81
gMVP		0.87
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs537377921; hg19: chr7-124469308;