16-75540018-G-T

Position:

chr16-75540018-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001077418.3(TMEM231):c.927C>A(p.Asp309Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,612,506 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D309V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 10 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.262

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060337186).

BP6

Variant 16-75540018-G-T is Benign according to our data. Variant chr16-75540018-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 786835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75540018-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00176 (267/152086) while in subpopulation NFE AF= 0.00281 (191/68040). AF 95% confidence interval is 0.00248. There are 2 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM231	NM_001077418.3 linkuse as main transcript	c.927C>A	p.Asp309Glu	missense_variant	7/7	ENST00000258173.11
TMEM231	NM_001077416.2 linkuse as main transcript	c.1086C>A	p.Asp362Glu	missense_variant	6/6
TMEM231	NR_074083.2 linkuse as main transcript	n.1093C>A		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM231	ENST00000258173.11 linkuse as main transcript	c.927C>A	p.Asp309Glu	missense_variant	7/7	1	NM_001077418.3	P1	Q9H6L2-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

267

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00172

AC:

426

AN:

248010

Hom.:

AF XY:

0.00164

AC XY:

221

AN XY:

134560

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.000699

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000986

Gnomad FIN exome

AF:

0.00237

Gnomad NFE exome

AF:

0.00278

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00224

AC:

3267

AN:

1460420

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

1558

AN XY:

726460

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000581

Gnomad4 FIN exome

AF:

0.00257

Gnomad4 NFE exome

AF:

0.00262

Gnomad4 OTH exome

AF:

0.00222

GnomAD4 genome

AF:

0.00176

AC:

267

AN:

152086

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000653

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00211

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000517

AC:

ESP6500EA

AF:

0.00181

AC:

ExAC

AF:

0.00194

AC:

234

EpiCase

AF:

0.00338

EpiControl

AF:

0.00160

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TMEM231: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	- -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.013

DANN

Benign

0.58

DEOGEN2

Benign

0.00076

T;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.28

T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.0060

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.85

N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

0.42

N;.;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.015

MutPred

0.35

Gain of helix (P = 0.0425);.;.;

MVP

0.030

MPC

0.0080

ClinPred

0.0010

GERP RS

-4.4

Varity_R

0.026

gMVP

0.24

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