Genetic Variant POTEH:p.Ser149Thr (chr22-15690523-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001136213.1(POTEH):c.446G>C(p.Ser149Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000776 in 128,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S149N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000078 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POTEH
NM_001136213.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.78

Publications

0 publications found

Variant links:

Genes affected

POTEH (HGNC:133): (POTE ankyrin domain family member H) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

POTEH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08778319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POTEH	NM_001136213.1 link	c.446G>C	p.Ser149Thr	missense_variant	Exon 1 of 11	ENST00000343518.11	NP_001129685.1	Q6S545-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POTEH	ENST00000343518.11 link	c.446G>C	p.Ser149Thr	missense_variant	Exon 1 of 11	5	NM_001136213.1	ENSP00000340610.6		Q6S545-1
POTEH	ENST00000452800.1 link	n.278G>C		non_coding_transcript_exon_variant	Exon 1 of 12	5		ENSP00000442107.1		H0YG78

Frequencies

GnomAD3 genomes

AF:

0.00000776

AC:

AN:

128808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000177

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000700

AC:

AN:

1286338

Hom.:

Cov.:

AF XY:

0.0000109

AC XY:

AN XY:

642474

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30634

American (AMR)

AF:

0.00

AC:

AN:

38680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23224

East Asian (EAS)

AF:

0.00

AC:

AN:

38538

South Asian (SAS)

AF:

0.00

AC:

AN:

82272

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5194

European-Non Finnish (NFE)

AF:

0.00000933

AC:

AN:

964292

Other (OTH)

AF:

0.00

AC:

AN:

53764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000845285), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000776

AC:

AN:

128912

Hom.:

Cov.:

AF XY:

0.0000158

AC XY:

AN XY:

63202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35620

American (AMR)

AF:

0.00

AC:

AN:

12474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2968

East Asian (EAS)

AF:

0.00

AC:

AN:

4920

South Asian (SAS)

AF:

0.00

AC:

AN:

4260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0000177

AC:

AN:

56540

Other (OTH)

AF:

0.00

AC:

AN:

1808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.2

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0066

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.0015

MetaRNN

Benign

0.088

T;T

MetaSVM

Benign

-1.0

PhyloP100

-3.8

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

N;.

Sift

Uncertain

0.016

D;.

Sift4G

Benign

0.090

T;D

Vest4

0.067

MutPred

0.35

.;Gain of catalytic residue at K116 (P = 0);

MVP

0.014

ClinPred

0.11

GERP RS

-1.1

PromoterAI

-0.0066

Neutral

(source)

gMVP

0.49

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over