16-75556001-G-C

Variant summary

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

The ENST00000568377.5(TMEM231):c.199C>G(p.Arg67Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,586,852 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: TMEM231 ENST00000568377.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0730

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=0.0053746104).
• BP6: Variant 16-75556001-G-C is Benign according to our data. Variant chr16-75556001-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 257329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000584 (89/152272) while in subpopulation SAS AF= 0.0118 (57/4828). AF 95% confidence interval is 0.00936. There are 1 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM231	NM_001077418.3	c.140-28C>G		intron_variant		ENST00000258173.11
TMEM231	NM_001077416.2	c.271C>G	p.Arg91Gly	missense_variant	1/6
TMEM231	NR_074083.2	n.183-28C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM231	ENST00000258173.11	c.140-28C>G		intron_variant		1	NM_001077418.3	P1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152154 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00199 AC: 406 AN: 204470 Hom.: 4 AF XY: 0.00258 AC XY: 289 AN XY: 111964

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000336

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.0000663

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000370

Gnomad OTH exome AF: 0.000773

GnomAD4 exome AF: 0.00111 AC: 1598 AN: 1434580 Hom.: 19 Cov.: 30 AF XY: 0.00145 AC XY: 1033 AN XY: 710864

Gnomad4 AFR exome AF: 0.000275

Gnomad4 AMR exome AF: 0.0000243

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000408

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152272 Hom.: 1 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74456

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000287

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000487 AC: 4

ExAC AF: 0.00193 AC: 231

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 21, 2017	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

TMEM231: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	3.6
Dann	Benign	0.42
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
Sift4G	Uncertain	0.0090	D
Vest4		0.11
MVP		0.061
MPC		0.95
ClinPred		0.016	T
GERP RS		-2.9

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: rs375353411; hg19: chr16-75589899;