rs116916706

Variant names:

• chr7-124851918-C-A
• rs116916706
• NM_015450.3:c.903G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-124851918-C-A
• chr7-124851918-C-G
• chr7-124851918-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015450.3(POT1):​c.903G>T​(p.Gln301His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00481 in 1,611,322 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q301K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (23 hom.)
• Consequence: POT1 NM_015450.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -0.0730
• Publications: 12 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039791167).
• BP6: Variant 7-124851918-C-A is Benign according to our data. Variant chr7-124851918-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475112.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.003 (457/152258) while in subpopulation NFE AF = 0.00474 (322/67988). AF 95% confidence interval is 0.00431. There are 0 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 23 AR,AD gene

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.903G>T	p.Gln301His	missense	Exon 11 of 19	NP_056265.2	Q9NUX5-1
	POT1	NM_001042594.2		c.510G>T	p.Gln170His	missense	Exon 10 of 18	NP_001036059.1	A8MTK3
	POT1	NR_003102.2		n.1346G>T		non_coding_transcript_exon	Exon 11 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	ENST00000357628.8	TSL:2 MANE Select	c.903G>T	p.Gln301His	missense	Exon 11 of 19	ENSP00000350249.3	Q9NUX5-1
	POT1	ENST00000607932.5	TSL:1	n.903G>T		non_coding_transcript_exon	Exon 7 of 14	ENSP00000476506.1	Q5MJ34
	POT1	ENST00000608057.5	TSL:1	n.903G>T		non_coding_transcript_exon	Exon 7 of 16	ENSP00000476371.1	Q5MJ35

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 459 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00275 AC: 691 AN: 250894 AF XY: 0.00302

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00430

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00500 AC: 7294 AN: 1459064 Hom.: 23 Cov.: 29 AF XY: 0.00490 AC XY: 3555 AN XY: 726050

African (AFR) AF: 0.000928 AC: 31 AN: 33400

American (AMR) AF: 0.00123 AC: 55 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00208 AC: 179 AN: 86126

European-Finnish (FIN) AF: 0.00365 AC: 195 AN: 53408

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5688

European-Non Finnish (NFE) AF: 0.00586 AC: 6503 AN: 1109860

Other (OTH) AF: 0.00544 AC: 328 AN: 60282

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.00278 AC XY: 207 AN XY: 74456

African (AFR) AF: 0.00144 AC: 60 AN: 41560

American (AMR) AF: 0.00137 AC: 21 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00474 AC: 322 AN: 67988

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00340 Hom.: 3

Bravo AF: 0.00271

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.00260 AC: 315

Asia WGS AF: 0.00260 AC: 10 AN: 3476

EpiCase AF: 0.00409

EpiControl AF: 0.00374

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	3	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	POT1-related disorder (1)
-	-	1	Tumor predisposition syndrome 3 (1)
-	-	1	Tumor predisposition syndrome 3;C5830496:Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8;C5830497:Cerebroretinal microangiopathy with calcifications and cysts 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.073
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.14	T
Sift4G	Uncertain	0.057	T
Polyphen		0.97	D
Vest4		0.23
MutPred		0.25		Gain of catalytic residue at D304 (P = 0.061)
MVP		0.60
MPC		0.24
ClinPred		0.017	T
GERP RS		-0.75
Varity_R		0.039
gMVP		0.52
Mutation Taster		=92/8	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: rs116916706; hg19: chr7-124491972;