rs199605221

Positions:

chr16-75540154-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_001077418.3(TMEM231):c.791A>C(p.Glu264Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000974 in 1,613,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.45

Variant links:

Genes affected

TMEM231 (HGNC:37234): (transmembrane protein 231) This gene encodes a transmembrane protein, which is a component of the B9 complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in this gene cause Joubert syndrome (JBTS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

TMEM231 links:

Genome browser will be placed here

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;

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.001 (1468/1460974) while in subpopulation NFE AF= 0.00119 (1324/1111542). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4_exome. There are 724 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM231	NM_001077418.3 linkuse as main transcript	c.791A>C	p.Glu264Ala	missense_variant	7/7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2 linkuse as main transcript	c.950A>C	p.Glu317Ala	missense_variant	6/6		NP_001070884.2
TMEM231	NR_074083.2 linkuse as main transcript	n.957A>C		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11 linkuse as main transcript	c.791A>C	p.Glu264Ala	missense_variant	7/7	1	NM_001077418.3	ENSP00000258173	P1	Q9H6L2-1

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000525

AC:

130

AN:

247402

Hom.:

AF XY:

0.000506

AC XY:

AN XY:

134350

show subpopulations

Gnomad AFR exome

AF:

0.000648

Gnomad AMR exome

AF:

0.000350

Gnomad ASJ exome

AF:

0.000499

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000822

Gnomad OTH exome

AF:

0.000667

GnomAD4 exome

AF:

0.00100

AC:

1468

AN:

1460974

Hom.:

Cov.:

AF XY:

0.000996

AC XY:

724

AN XY:

726778

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.000515

Gnomad4 ASJ exome

AF:

0.000881

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0000938

Gnomad4 NFE exome

AF:

0.00119

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152276

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000926

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000846

Hom.:

Bravo

AF:

0.000759

ESP6500AA

AF:

0.000258

AC:

ESP6500EA

AF:

0.000847

AC:

ExAC

AF:

0.000438

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000712

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 317 of the TMEM231 protein (p.Glu317Ala). This variant is present in population databases (rs199605221, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TMEM231-related conditions. ClinVar contains an entry for this variant (Variation ID: 286672). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2022

The c.878A>C (p.E293A) alteration is located in exon 6 (coding exon 6) of the TMEM231 gene. This alteration results from a A to C substitution at nucleotide position 878, causing the glutamic acid (E) at amino acid position 293 to be replaced by an alanine (A). 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

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.;D

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Uncertain

-0.099

MutationAssessor

Uncertain

2.6

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.2

D;.;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.012

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

D;.;.

Vest4

0.88

MVP

0.56

MPC

0.047

ClinPred

0.072

GERP RS

4.3

Varity_R

0.46

gMVP

0.83

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