rs3743602

Variant names:

• chr16-75556215-C-G
• rs3743602
• NM_001077418.3:c.-6G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-75556215-C-G
• chr16-75556215-C-T

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.-6G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,416,130 control chromosomes in the GnomAD database, including 40,147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3813 hom., cov: 33)
  • Exomes 𝑓: 0.24 (36334 hom.)
• Consequence: TMEM231 NM_001077418.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.182
• Publications: 12 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

ENSG00000259992 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-75556215-C-G is Benign according to our data. Variant chr16-75556215-C-G is described in ClinVar as Benign. ClinVar VariationId is 257330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.-6G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077418.3	c.-6G>C		5_prime_UTR_variant	Exon 1 of 7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.57G>C	p.Arg19Arg	synonymous_variant	Exon 1 of 6		NP_001070884.2
TMEM231	NR_074083.2	n.38G>C		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.-6G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.-16G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.-6G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.-6G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.-6G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	5		ENSP00000455520.1
TMEM231	ENST00000562410.5	n.-6G>C		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.-6G>C		non_coding_transcript_exon_variant	Exon 1 of 7	5		ENSP00000455520.1
TMEM231	ENST00000258173.11	c.-6G>C		5_prime_UTR_variant	Exon 1 of 7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.-16G>C		5_prime_UTR_variant	Exon 1 of 6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.-6G>C		5_prime_UTR_variant	Exon 1 of 6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.-6G>C		5_prime_UTR_variant	Exon 1 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.-6G>C		5_prime_UTR_variant	Exon 1 of 7	5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33136 AN: 152088 Hom.: 3808 Cov.: 33

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.218 AC: 11887 AN: 54578 AF XY: 0.221

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.241

Gnomad FIN exome AF: 0.280

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.237 AC: 299906 AN: 1263924 Hom.: 36334 Cov.: 32 AF XY: 0.235 AC XY: 144285 AN XY: 613532

African (AFR) AF: 0.162 AC: 4100 AN: 25300

American (AMR) AF: 0.127 AC: 2226 AN: 17494

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 2578 AN: 18160

East Asian (EAS) AF: 0.244 AC: 7391 AN: 30284

South Asian (SAS) AF: 0.167 AC: 10096 AN: 60598

European-Finnish (FIN) AF: 0.301 AC: 9568 AN: 31798

Middle Eastern (MID) AF: 0.181 AC: 920 AN: 5096

European-Non Finnish (NFE) AF: 0.246 AC: 251400 AN: 1022712

Other (OTH) AF: 0.222 AC: 11627 AN: 52482

GnomAD4 genome AF: 0.218 AC: 33150 AN: 152206 Hom.: 3813 Cov.: 33 AF XY: 0.217 AC XY: 16129 AN XY: 74408

African (AFR) AF: 0.169 AC: 7025 AN: 41552

American (AMR) AF: 0.161 AC: 2468 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3466

East Asian (EAS) AF: 0.253 AC: 1308 AN: 5168

South Asian (SAS) AF: 0.169 AC: 818 AN: 4830

European-Finnish (FIN) AF: 0.302 AC: 3200 AN: 10582

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17075 AN: 67990

Other (OTH) AF: 0.199 AC: 420 AN: 2108

Alfa AF: 0.239 Hom.: 563

Bravo AF: 0.204

Asia WGS AF: 0.238 AC: 825 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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;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	-0.71
CADD	Benign	6.3
DANN	Benign	0.86
PhyloP100		-0.18
PromoterAI		0.064	Neutral
Mutation Taster		=300/0	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: rs3743602; hg19: chr16-75590113; COSMIC: COSV107247587; COSMIC: COSV107247587;