22-15690523-G-A

Variant names:

• chr22-15690523-G-A
• rs772295021
• NM_001136213.1:c.446G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.78
• Publications: 1 publications found

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]

ACMG classification

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	c.446G>A	p.Ser149Asn	missense_variant	Exon 1 of 11	ENST00000343518.11	NP_001129685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POTEH	ENST00000343518.11	c.446G>A	p.Ser149Asn	missense_variant	Exon 1 of 11	5	NM_001136213.1	ENSP00000340610.6
POTEH	ENST00000452800.1	n.278G>A		non_coding_transcript_exon_variant	Exon 1 of 12	5		ENSP00000442107.1

Frequencies

GnomAD3 genomes AF: 0.0000155 AC: 2 AN: 128808 Hom.: 1 Cov.: 26

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: 3 AN: 226412 AF XY: 0.0000163

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: 70 AN: 1286332 Hom.: 21 Cov.: 36 AF XY: 0.0000607 AC XY: 39 AN XY: 642470

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

African (AFR) AF: 0.00 AC: 0 AN: 30634

American (AMR) AF: 0.00 AC: 0 AN: 38680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23224

East Asian (EAS) AF: 0.00 AC: 0 AN: 38538

South Asian (SAS) AF: 0.00 AC: 0 AN: 82272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5194

European-Non Finnish (NFE) AF: 0.0000622 AC: 60 AN: 964286

Other (OTH) AF: 0.000186 AC: 10 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.

GnomAD4 genome AF: 0.0000155 AC: 2 AN: 128808 Hom.: 1 Cov.: 26 AF XY: 0.0000317 AC XY: 2 AN XY: 63090

African (AFR) AF: 0.0000563 AC: 2 AN: 35508

American (AMR) AF: 0.00 AC: 0 AN: 12458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2968

East Asian (EAS) AF: 0.00 AC: 0 AN: 4932

South Asian (SAS) AF: 0.00 AC: 0 AN: 4262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56542

Other (OTH) AF: 0.00 AC: 0 AN: 1792

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.4
DANN	Benign	0.84
DEOGEN2	Benign	0.0090	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00033	N
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-3.8
PrimateAI	Benign	0.35	T
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	T
GERP RS		-1.1
PromoterAI		0.0027	Neutral
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

Other links and lift over

dbSNP: rs772295021; hg19: chr14-19553751; COSMIC: COSV58883811;