Genetic Variant NM_001136213.1:c.446G>A (chr22-15690523-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001136213.1(POTEH):c.446G>A(p.Ser149Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,415,140 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000016 ( 1 hom., cov: 26)

Exomes 𝑓: 0.000054 ( 21 hom. )

Consequence

POTEH
NM_001136213.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.78

Publications

1 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08375889).

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POTEH	NM_001136213.1 link	c.446G>A	p.Ser149Asn	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>A	p.Ser149Asn	missense_variant	Exon 1 of 11	5	NM_001136213.1	ENSP00000340610.6		Q6S545-1
POTEH	ENST00000452800.1 link	n.278G>A		non_coding_transcript_exon_variant	Exon 1 of 12	5		ENSP00000442107.1		H0YG78

Frequencies

GnomAD3 genomes

AF:

0.0000155

AC:

AN:

128808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000563

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000133

AC:

AN:

226412

AF XY:

0.0000163

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000300

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000544

AC:

AN:

1286332

Hom.:

Cov.:

AF XY:

0.0000607

AC XY:

AN XY:

642470

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:

0.0000622

AC:

AN:

964286

Other (OTH)

AF:

0.000186

AC:

AN:

53764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000100686), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000155

AC:

AN:

128808

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

63090

show subpopulations

African (AFR)

AF:

0.0000563

AC:

AN:

35508

American (AMR)

AF:

0.00

AC:

AN:

12458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2968

East Asian (EAS)

AF:

0.00

AC:

AN:

4932

South Asian (SAS)

AF:

0.00

AC:

AN:

4262

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

56542

Other (OTH)

AF:

0.00

AC:

AN:

1792

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.446G>A (p.S149N) alteration is located in exon 1 (coding exon 1) of the POTEH gene. This alteration results from a G to A substitution at nucleotide position 446, causing the serine (S) at amino acid position 149 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.4

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0090

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.00033

LIST_S2

Benign

0.55

T;T

M_CAP

Benign

0.0018

MetaRNN

Benign

0.084

T;T

MetaSVM

Benign

-1.0

PhyloP100

-3.8

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

N;.

Sift

Uncertain

0.029

D;.

Sift4G

Benign

0.14

T;T

Vest4

0.076

MutPred

0.36

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

MVP

0.014

ClinPred

0.11

GERP RS

-1.1

PromoterAI

0.0027

Neutral

(source)

gMVP

0.49

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over