rs201636741

chr16-75545436-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001077418.3(TMEM231):c.498G>A(p.Pro166=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,605,626 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 21)
  • Exomes 𝑓: 0.00047 (3 hom.)
• Consequence: TMEM231 NM_001077418.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.67

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 16-75545436-C-T is Benign according to our data. Variant chr16-75545436-C-T is described in ClinVar as [Benign]. Clinvar id is 385987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00428 (638/149212) while in subpopulation AFR AF= 0.0144 (583/40402). AF 95% confidence interval is 0.0135. There are 5 homozygotes in gnomad4. There are 315 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM231	NM_001077418.3	c.498G>A	p.Pro166=	synonymous_variant	4/7	ENST00000258173.11
TMEM231	NM_001077416.2	c.657G>A	p.Pro219=	synonymous_variant	3/6
TMEM231	NR_074083.2	n.664G>A		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM231	ENST00000258173.11	c.498G>A	p.Pro166=	synonymous_variant	4/7	1	NM_001077418.3	P1

Frequencies

GnomAD3 genomes AF: 0.00429 AC: 639 AN: 149096 Hom.: 5 Cov.: 21

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00291

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000223

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000741

Gnomad OTH AF: 0.00297

GnomAD3 exomes AF: 0.00121 AC: 300 AN: 246996 Hom.: 0 AF XY: 0.000999 AC XY: 134 AN XY: 134068

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000504

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000466 AC: 678 AN: 1456414 Hom.: 3 Cov.: 28 AF XY: 0.000407 AC XY: 295 AN XY: 724352

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.00162

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000334

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00428 AC: 638 AN: 149212 Hom.: 5 Cov.: 21 AF XY: 0.00434 AC XY: 315 AN XY: 72662

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00290

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000223

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000741

Gnomad4 OTH AF: 0.00294

Alfa AF: 0.00217 Hom.: 0

Bravo AF: 0.00487

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 21, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	14
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.76		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201636741; hg19: chr16-75579334;