chr16-75540017-A-C

Position:

chr16-75540017-A-C

Variant summary

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

The ENST00000258173.11(TMEM231):c.928T>G(p.Leu310Val) 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 1,612,450 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L310L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 10 hom. )

Consequence

TMEM231
ENST00000258173.11 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.06

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:

ENSG00000260092 (HGNC:):

ENSG00000260092 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=0.0049693584).

BP6

Variant 16-75540017-A-C is Benign according to our data. Variant chr16-75540017-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 786834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75540017-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00176 (267/152098) while in subpopulation NFE AF= 0.00281 (191/68036). 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	Protein	UniProt
TMEM231	NM_001077418.3 linkuse as main transcript	c.928T>G	p.Leu310Val	missense_variant	7/7	ENST00000258173.11	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2 linkuse as main transcript	c.1087T>G	p.Leu363Val	missense_variant	6/6		NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2 linkuse as main transcript	n.1094T>G		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM231	ENST00000258173.11 linkuse as main transcript	c.928T>G	p.Leu310Val	missense_variant	7/7	1	NM_001077418.3	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000568377.5 linkuse as main transcript	c.1015T>G	p.Leu339Val	missense_variant	6/6	1		ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000565067.5 linkuse as main transcript	c.784T>G	p.Leu262Val	missense_variant	6/6	5		ENSP00000457254.1	H3BTN6
TMEM231	ENST00000562410.5 linkuse as main transcript	n.*730T>G		non_coding_transcript_exon_variant	7/7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 linkuse as main transcript	n.*308T>G		non_coding_transcript_exon_variant	7/7	5		ENSP00000455520.1	H3BPY4
TMEM231	ENST00000562410.5 linkuse as main transcript	n.*730T>G		3_prime_UTR_variant	7/7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 linkuse as main transcript	n.*308T>G		3_prime_UTR_variant	7/7	5		ENSP00000455520.1	H3BPY4
ENSG00000260092	ENST00000460606.1 linkuse as main transcript	n.157+2585T>G		intron_variant		1		ENSP00000457544.1	H3BUA1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

267

AN:

151980

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:

0.00171

AC:

423

AN:

247936

Hom.:

AF XY:

0.00163

AC XY:

219

AN XY:

134502

show subpopulations

Gnomad AFR exome

AF:

0.000389

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.000700

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000987

Gnomad FIN exome

AF:

0.00233

Gnomad NFE exome

AF:

0.00276

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00224

AC:

3271

AN:

1460352

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

1559

AN XY:

726414

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:

0.00255

Gnomad4 NFE exome

AF:

0.00263

Gnomad4 OTH exome

AF:

0.00219

GnomAD4 genome

AF:

0.00176

AC:

267

AN:

152098

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74386

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:

0.000748

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000518

AC:

ESP6500EA

AF:

0.00157

AC:

ExAC

AF:

0.00194

AC:

234

EpiCase

AF:

0.00338

EpiControl

AF:

0.00160

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	- -
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	-	- -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2022

- -

TMEM231-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.013

DANN

Benign

0.27

DEOGEN2

Benign

0.00046

T;.;T

Eigen

Benign

-2.6

Eigen_PC

Benign

-2.7

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.12

T;T;T

M_CAP

Benign

0.068

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.060

N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.28

N;.;N

REVEL

Benign

0.077

Sift

Benign

0.79

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.033

MVP

0.030

MPC

0.0078

ClinPred

0.00014

GERP RS

-7.7

Varity_R

0.020

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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