Genetic Variant TMEM88B:p.Ala105Pro (chr1-1427608-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001146685.2(TMEM88B):c.313G>C(p.Ala105Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000421 in 1,186,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A105V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000030 ( 0 hom., cov: 14)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

TMEM88B
NM_001146685.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

Variant links:

Genes affected

TMEM88B (HGNC:37099): (transmembrane protein 88B) Predicted to enable PDZ domain binding activity. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM88B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38355514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM88B	NM_001146685.2 link	c.313G>C	p.Ala105Pro	missense_variant	Exon 2 of 2	ENST00000378821.4	NP_001140157.1	A6NKF7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM88B	ENST00000378821.4 link	c.313G>C	p.Ala105Pro	missense_variant	Exon 2 of 2	2	NM_001146685.2	ENSP00000455099.1		A6NKF7

Frequencies

GnomAD3 genomes

AF:

0.0000300

AC:

AN:

99898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000400

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000440

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000778

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

61892

Hom.:

AF XY:

0.00

AC XY:

AN XY:

36642

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000919

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1087008

Hom.:

Cov.:

AF XY:

0.00000189

AC XY:

AN XY:

528174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000629

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000247

GnomAD4 genome

AF:

0.0000300

AC:

AN:

99952

Hom.:

Cov.:

AF XY:

0.0000214

AC XY:

AN XY:

46740

show subpopulations

Gnomad4 AFR

AF:

0.0000400

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000439

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000768

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313G>C (p.A105P) alteration is located in exon 2 (coding exon 2) of the TMEM88B gene. This alteration results from a G to C substitution at nucleotide position 313, causing the alanine (A) at amino acid position 105 to be replaced by a proline (P). 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

Uncertain

0.47

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.48

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.38

MutationAssessor

Uncertain

2.2

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-2.9

Sift

Uncertain

0.027

Sift4G

Uncertain

0.048

Polyphen

0.96

Vest4

0.49

MVP

0.64

GERP RS

0.45

Varity_R

0.56

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over