Genetic Variant TMEM232:p.Pro529His (chr5-110528705-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001039763.4(TMEM232):c.1586C>A(p.Pro529His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,382,418 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMEM232
NM_001039763.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.47

Publications

0 publications found

Variant links:

Genes affected

TMEM232 (HGNC:37270): (transmembrane protein 232) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM232 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM232	NM_001039763.4 link	c.1586C>A	p.Pro529His	missense_variant	Exon 12 of 14	ENST00000455884.7	NP_001034852.3	C9JQI7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM232	ENST00000455884.7 link	c.1586C>A	p.Pro529His	missense_variant	Exon 12 of 14	2	NM_001039763.4	ENSP00000401477.2	C9JQI7-1
TMEM232	ENST00000512003.7 link	n.*997+39742C>A		intron_variant	Intron 9 of 10	1		ENSP00000427785.2	E5RG73
TMEM232	ENST00000515518.6 link	n.1375+39742C>A		intron_variant	Intron 10 of 12	1
TMEM232	ENST00000508571.6 link	n.1018+39742C>A		intron_variant	Intron 5 of 5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1382418

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

682148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31564

American (AMR)

AF:

0.00

AC:

AN:

35580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25140

East Asian (EAS)

AF:

0.00

AC:

AN:

35590

South Asian (SAS)

AF:

0.00

AC:

AN:

79000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1078160

Other (OTH)

AF:

0.00

AC:

AN:

57824

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1586C>A (p.P529H) alteration is located in exon 12 (coding exon 11) of the TMEM232 gene. This alteration results from a C to A substitution at nucleotide position 1586, causing the proline (P) at amino acid position 529 to be replaced by a histidine (H). 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

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.067

Eigen

Benign

0.00091

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.44

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.9

PhyloP100

3.5

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.30

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.57

MutPred

0.51

Loss of catalytic residue at P529 (P = 0.0146);

MVP

0.17

ClinPred

0.91

GERP RS

4.4

Varity_R

0.16

gMVP

0.24

Mutation Taster

=80/20

polymorphism

(source)

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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5-110528705-G-T

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