16-75540017-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077418.3(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 NM_001077418.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.06

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 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 GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM231	NM_001077418.3	c.928T>G	p.Leu310Val	missense_variant	7/7	ENST00000258173.11
TMEM231	NM_001077416.2	c.1087T>G	p.Leu363Val	missense_variant	6/6
TMEM231	NR_074083.2	n.1094T>G		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM231	ENST00000258173.11	c.928T>G	p.Leu310Val	missense_variant	7/7	1	NM_001077418.3	P1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 151980 Hom.: 2 Cov.: 32

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.: 3 AF XY: 0.00163 AC XY: 219 AN XY: 134502

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.: 10 Cov.: 31 AF XY: 0.00215 AC XY: 1559 AN XY: 726414

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.: 2 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74386

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.: 0

Bravo AF: 0.00162

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000518 AC: 2

ESP6500EA AF: 0.00157 AC: 13

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

Submissions by phenotype

not provided Benign:2

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	Jun 01, 2023	TMEM231: BP4, BS2 -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2022

- -

TMEM231-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	T
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	N
LIST_S2	Benign	0.12	T;T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.060	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
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	T
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

Other links and lift over

dbSNP: rs182008317; hg19: chr16-75573915; COSMIC: COSV50738381; COSMIC: COSV50738381;