16-75545335-A-T

Variant names:

• chr16-75545335-A-T
• rs2738801
• NM_001077418.3:c.582+17T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001077418.3(TMEM231):​c.582+17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,603,564 control chromosomes in the GnomAD database, including 52,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5240 hom., cov: 27)
  • Exomes 𝑓: 0.25 (47325 hom.)
• Consequence: TMEM231 NM_001077418.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.851
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 20

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome III

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000260092 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-75545335-A-T is Benign according to our data. Variant chr16-75545335-A-T is described in ClinVar as Benign. ClinVar VariationId is 257331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.582+17T>A		intron_variant	Intron 4 of 6	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.741+17T>A		intron_variant	Intron 3 of 5		NP_001070884.2
TMEM231	NR_074083.2	n.748+17T>A		intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.582+17T>A		intron_variant	Intron 4 of 6	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.669+17T>A		intron_variant	Intron 3 of 5	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.438+491T>A		intron_variant	Intron 3 of 5	5		ENSP00000457254.1
ENSG00000260092	ENST00000460606.1	n.75+17T>A		intron_variant	Intron 1 of 4	1		ENSP00000457544.1
TMEM231	ENST00000562410.5	n.*384+17T>A		intron_variant	Intron 4 of 6	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.544+17T>A		intron_variant	Intron 4 of 6	5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39381 AN: 151826 Hom.: 5234 Cov.: 27

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.239 AC: 58635 AN: 245504 AF XY: 0.242

Gnomad AFR exome AF: 0.289

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.252 AC: 366354 AN: 1451620 Hom.: 47325 Cov.: 32 AF XY: 0.252 AC XY: 181783 AN XY: 720712

African (AFR) AF: 0.286 AC: 9461 AN: 33056

American (AMR) AF: 0.131 AC: 5690 AN: 43554

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4490 AN: 25844

East Asian (EAS) AF: 0.215 AC: 8492 AN: 39454

South Asian (SAS) AF: 0.232 AC: 19880 AN: 85708

European-Finnish (FIN) AF: 0.311 AC: 16578 AN: 53286

Middle Eastern (MID) AF: 0.232 AC: 1322 AN: 5694

European-Non Finnish (NFE) AF: 0.258 AC: 285583 AN: 1105152

Other (OTH) AF: 0.248 AC: 14858 AN: 59872

GnomAD4 genome AF: 0.259 AC: 39410 AN: 151944 Hom.: 5240 Cov.: 27 AF XY: 0.257 AC XY: 19111 AN XY: 74260

African (AFR) AF: 0.283 AC: 11710 AN: 41426

American (AMR) AF: 0.185 AC: 2822 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 598 AN: 3468

East Asian (EAS) AF: 0.228 AC: 1183 AN: 5178

South Asian (SAS) AF: 0.227 AC: 1092 AN: 4806

European-Finnish (FIN) AF: 0.309 AC: 3264 AN: 10552

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17828 AN: 67958

Other (OTH) AF: 0.236 AC: 499 AN: 2110

Alfa AF: 0.178 Hom.: 540

Bravo AF: 0.249

Asia WGS AF: 0.286 AC: 992 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.031
DANN	Benign	0.36
PhyloP100		-0.85
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2738801; hg19: chr16-75579233; COSMIC: COSV50737811; COSMIC: COSV50737811;