16-75540054-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001077418.3(TMEM231):c.891G>A(p.Val297=) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.364

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 -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 id is 212404.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM231	NM_001077418.3	c.891G>A	p.Val297=	synonymous_variant	7/7	ENST00000258173.11
TMEM231	NM_001077416.2	c.1050G>A	p.Val350=	synonymous_variant	6/6
TMEM231	NR_074083.2	n.1057G>A		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM231	ENST00000258173.11	c.891G>A	p.Val297=	synonymous_variant	7/7	1	NM_001077418.3	P1

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 690 AN: 152210 Hom.: 3 Cov.: 32

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

GnomAD3 exomes AF: 0.00753 AC: 1873 AN: 248802 Hom.: 24 AF XY: 0.00907 AC XY: 1224 AN XY: 135000

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 SAS exome AF: 0.0290

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.: 74 Cov.: 31 AF XY: 0.00670 AC XY: 4872 AN XY: 726954

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.00586

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0290

Gnomad4 FIN exome AF: 0.00300

Gnomad4 NFE exome AF: 0.00455

Gnomad4 OTH exome AF: 0.00565

GnomAD4 genome AF: 0.00454 AC: 692 AN: 152328 Hom.: 3 Cov.: 32 AF XY: 0.00505 AC XY: 376 AN XY: 74480

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00548

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00512 Hom.: 0

Bravo AF: 0.00408

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00546

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 10, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	4.6
Dann	Benign	0.79

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: rs149888762; hg19: chr16-75573952;