rs115739052

Positions:

• chr16-75556260-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001077416.2(TMEM231):​c.12G>A​(p.Arg4Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,382,836 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: TMEM231 NM_001077416.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.110

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]

TMEM231 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-75556260-C-T is Benign according to our data. Variant chr16-75556260-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 516234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0122 (1862/152332) while in subpopulation AFR AF= 0.0415 (1727/41580). AF 95% confidence interval is 0.0399. There are 43 homozygotes in gnomad4. There are 853 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM231	NM_001077416.2	c.12G>A	p.Arg4Arg	synonymous_variant	1/6		NP_001070884.2
TMEM231	NM_001077418.3	c.-51G>A		upstream_gene_variant		ENST00000258173.11	NP_001070886.1
TMEM231	NR_074083.2	n.-8G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000562410.5	n.-51G>A		non_coding_transcript_exon_variant	1/7	1		ENSP00000454582.1
TMEM231	ENST00000562410.5	n.-51G>A		5_prime_UTR_variant	1/7	1		ENSP00000454582.1
TMEM231	ENST00000258173.11	c.-51G>A		upstream_gene_variant		1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.-61G>A		upstream_gene_variant		1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.-51G>A		upstream_gene_variant		5		ENSP00000457254.1
TMEM231	ENST00000570006.5	n.-51G>A		upstream_gene_variant		5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1856 AN: 152214 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.00107 AC: 1318 AN: 1230504 Hom.: 27 Cov.: 31 AF XY: 0.000946 AC XY: 563 AN XY: 594890

Gnomad4 AFR exome AF: 0.0420

Gnomad4 AMR exome AF: 0.00343

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000727

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.0122 AC: 1862 AN: 152332 Hom.: 43 Cov.: 32 AF XY: 0.0115 AC XY: 853 AN XY: 74480

Gnomad4 AFR AF: 0.0415

Gnomad4 AMR AF: 0.00679

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00567 Hom.: 6

Bravo AF: 0.0135

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.91

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: rs115739052; hg19: chr16-75590158;