16-75556194-G-C

Variant names:

• chr16-75556194-G-C
• rs3743601
• NM_001077418.3:c.16C>G

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.16C>G​(p.Leu6Val) variant causes a missense change. The variant allele was found at a frequency of 0.0938 in 1,485,022 control chromosomes in the GnomAD database, including 19,435 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L6I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (2663 hom., cov: 33)
  • Exomes 𝑓: 0.091 (16772 hom.)
• Consequence: TMEM231 NM_001077418.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.96
• Publications: 23 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 (MetaRNN=1.8012524E-5).
• BP6: Variant 16-75556194-G-C is Benign according to our data. Variant chr16-75556194-G-C is described in ClinVar as Benign. ClinVar VariationId is 130587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.16C>G	p.Leu6Val	missense_variant	Exon 1 of 7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.78C>G	p.Ser26Arg	missense_variant	Exon 1 of 6		NP_001070884.2
TMEM231	NR_074083.2	n.59C>G		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.16C>G	p.Leu6Val	missense_variant	Exon 1 of 7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.6C>G	p.Ser2Arg	missense_variant	Exon 1 of 6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.16C>G	p.Leu6Val	missense_variant	Exon 1 of 6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.16C>G		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.16C>G		non_coding_transcript_exon_variant	Exon 1 of 7	5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18175 AN: 152146 Hom.: 2652 Cov.: 33

Gnomad AFR AF: 0.0929

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.0581

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.210 AC: 24008 AN: 114184 AF XY: 0.196

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.438

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.751

Gnomad FIN exome AF: 0.0584

Gnomad NFE exome AF: 0.0520

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.0908 AC: 121014 AN: 1332758 Hom.: 16772 Cov.: 31 AF XY: 0.0945 AC XY: 61597 AN XY: 651754

African (AFR) AF: 0.0918 AC: 2616 AN: 28502

American (AMR) AF: 0.399 AC: 11201 AN: 28060

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 2394 AN: 20028

East Asian (EAS) AF: 0.719 AC: 25324 AN: 35242

South Asian (SAS) AF: 0.274 AC: 18876 AN: 68902

European-Finnish (FIN) AF: 0.0551 AC: 2035 AN: 36938

Middle Eastern (MID) AF: 0.0931 AC: 494 AN: 5304

European-Non Finnish (NFE) AF: 0.0486 AC: 51267 AN: 1054540

Other (OTH) AF: 0.123 AC: 6807 AN: 55242

GnomAD4 genome AF: 0.120 AC: 18216 AN: 152264 Hom.: 2663 Cov.: 33 AF XY: 0.132 AC XY: 9802 AN XY: 74438

African (AFR) AF: 0.0934 AC: 3879 AN: 41544

American (AMR) AF: 0.293 AC: 4482 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3472

East Asian (EAS) AF: 0.710 AC: 3671 AN: 5172

South Asian (SAS) AF: 0.304 AC: 1465 AN: 4822

European-Finnish (FIN) AF: 0.0581 AC: 617 AN: 10620

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0477 AC: 3244 AN: 68030

Other (OTH) AF: 0.127 AC: 268 AN: 2114

Alfa AF: 0.0786 Hom.: 1200

Bravo AF: 0.140

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0467 AC: 180

ESP6500AA AF: 0.0835 AC: 301

ESP6500EA AF: 0.0463 AC: 361

ExAC AF: 0.156 AC: 17902

Asia WGS AF: 0.449 AC: 1557 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 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

- -

Joubert syndrome 20 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.060	T;T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.000018	T;T
MetaSVM	Benign	-0.92	T
PhyloP100		4.0
PROVEAN	Benign	0.86	N;N
REVEL	Benign	0.099
Sift	Benign	1.0	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.021	B;.
Vest4		0.045
ClinPred		0.075	T
GERP RS		4.6
PromoterAI		0.043	Neutral
Varity_R		0.11
gMVP		0.46
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3743601; hg19: chr16-75590092; COSMIC: COSV50738700; COSMIC: COSV50738700;