rs377440297

chr16-75556081-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000568377.5(TMEM231):c.119C>T(p.Ser40Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000738 in 1,568,414 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S40S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (2 hom.)
• Consequence: TMEM231 ENST00000568377.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.61

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011699468).
• BP6: Variant 16-75556081-G-A is Benign according to our data. Variant chr16-75556081-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287699.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM231	NM_001077418.3	c.129C>T	p.Phe43=	synonymous_variant	1/7	ENST00000258173.11
TMEM231	NM_001077416.2	c.191C>T	p.Ser64Phe	missense_variant	1/6
TMEM231	NR_074083.2	n.172C>T		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM231	ENST00000258173.11	c.129C>T	p.Phe43=	synonymous_variant	1/7	1	NM_001077418.3	P1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000497 AC: 84 AN: 169150 Hom.: 0 AF XY: 0.000529 AC XY: 49 AN XY: 92612

Gnomad AFR exome AF: 0.000119

Gnomad AMR exome AF: 0.000266

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000408

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000676

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.000757 AC: 1072 AN: 1416054 Hom.: 2 Cov.: 30 AF XY: 0.000721 AC XY: 505 AN XY: 700348

Gnomad4 AFR exome AF: 0.0000931

Gnomad4 AMR exome AF: 0.000239

Gnomad4 ASJ exome AF: 0.00323

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000246

Gnomad4 FIN exome AF: 0.0000410

Gnomad4 NFE exome AF: 0.000844

Gnomad4 OTH exome AF: 0.000903

GnomAD4 genome AF: 0.000564 AC: 86 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000429 AC XY: 32 AN XY: 74506

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000472

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.000358 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2020	Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 09, 2017	- -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

TMEM231-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2022

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
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	13
Dann	Benign	0.95
Eigen	Benign	-0.15
Eigen_PC	Benign	0.014
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.74	T
Sift4G	Pathogenic	0.0	D
Vest4		0.21
MVP		0.14
MPC		1.8
ClinPred		0.094	T
GERP RS		4.5

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

Other links and lift over

dbSNP: rs377440297; hg19: chr16-75589979;