16-75540054-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001077418.3(TMEM231):c.891G>A(p.Val297Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00573 in 1,613,694 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 74 hom. )

Consequence

TMEM231
NM_001077418.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.364

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Joubert syndrome 20
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Joubert syndrome with oculorenal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
orofaciodigital syndrome III
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMEM231 links:

ENSG00000260092 (HGNC:):

ENSG00000260092 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 16-75540054-C-T is Benign according to our data. Variant chr16-75540054-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212404.

BP7

Synonymous conserved (PhyloP=-0.364 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00454 (692/152328) while in subpopulation SAS AF = 0.0261 (126/4834). AF 95% confidence interval is 0.0224. There are 3 homozygotes in GnomAd4. There are 376 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3 link	c.891G>A	p.Val297Val	synonymous_variant	Exon 7 of 7	ENST00000258173.11	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2 link	c.1050G>A	p.Val350Val	synonymous_variant	Exon 6 of 6		NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2 link	n.1057G>A		non_coding_transcript_exon_variant	Exon 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM231	ENST00000258173.11 link	c.891G>A	p.Val297Val	synonymous_variant	Exon 7 of 7	1	NM_001077418.3	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000568377.5 link	c.978G>A	p.Val326Val	synonymous_variant	Exon 6 of 6	1		ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000565067.5 link	c.747G>A	p.Val249Val	synonymous_variant	Exon 6 of 6	5		ENSP00000457254.1	H3BTN6
TMEM231	ENST00000562410.5 link	n.*693G>A		non_coding_transcript_exon_variant	Exon 7 of 7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.*271G>A		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000455520.1	H3BPY4
TMEM231	ENST00000562410.5 link	n.*693G>A		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.*271G>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000455520.1	H3BPY4
ENSG00000260092	ENST00000460606.1 link	n.157+2548G>A		intron_variant	Intron 2 of 4	1		ENSP00000457544.1	H3BUA1

Frequencies

GnomAD3 genomes

AF:

0.00453

AC:

690

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0256

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00547

Gnomad OTH

AF:

0.00672

GnomAD2 exomes

AF:

0.00753

AC:

1873

AN:

248802

AF XY:

0.00907

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.00328

Gnomad ASJ exome

AF:

0.00567

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.00223

Gnomad NFE exome

AF:

0.00636

Gnomad OTH exome

AF:

0.00746

GnomAD4 exome

AF:

0.00585

AC:

8555

AN:

1461366

Hom.:

Cov.:

AF XY:

0.00670

AC XY:

4872

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33470

American (AMR)

AF:

0.00322

AC:

144

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00586

AC:

153

AN:

26130

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0290

AC:

2504

AN:

86218

European-Finnish (FIN)

AF:

0.00300

AC:

160

AN:

53392

Middle Eastern (MID)

AF:

0.0257

AC:

148

AN:

5752

European-Non Finnish (NFE)

AF:

0.00455

AC:

5059

AN:

1111652

Other (OTH)

AF:

0.00565

AC:

341

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

413

825

1238

1650

2063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

384

576

768

960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00454

AC:

692

AN:

152328

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

376

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41580

American (AMR)

AF:

0.00333

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0261

AC:

126

AN:

4834

European-Finnish (FIN)

AF:

0.00301

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00548

AC:

373

AN:

68036

Other (OTH)

AF:

0.00617

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00483

Hom.:

Bravo

AF:

0.00408

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.00605

EpiControl

AF:

0.00546

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Aug 21, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 10, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

4.6

(source)

DANN

Benign

0.79

PhyloP100

-0.36

Mutation Taster

=100/0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over