16-75555881-C-T

Variant names:

• chr16-75555881-C-T
• rs753709447
• NM_001077418.3:c.232G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001077418.3(TMEM231):​c.232G>A​(p.Asp78Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,441,286 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D78Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (1 hom.)
• Consequence: TMEM231 NM_001077418.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.69
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001077418.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20489964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.232G>A	p.Asp78Asn	missense_variant	Exon 2 of 7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.391G>A	p.Asp131Asn	missense_variant	Exon 1 of 6		NP_001070884.2
TMEM231	NR_074083.2	n.275G>A		non_coding_transcript_exon_variant	Exon 2 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.232G>A	p.Asp78Asn	missense_variant	Exon 2 of 7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.319G>A	p.Asp107Asn	missense_variant	Exon 1 of 6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.232G>A	p.Asp78Asn	missense_variant	Exon 2 of 6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.232G>A		non_coding_transcript_exon_variant	Exon 2 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.232G>A		non_coding_transcript_exon_variant	Exon 2 of 7	5		ENSP00000455520.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441286 Hom.: 1 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 714646

African (AFR) AF: 0.00 AC: 0 AN: 32914

American (AMR) AF: 0.00 AC: 0 AN: 42200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25546

East Asian (EAS) AF: 0.00 AC: 0 AN: 38826

South Asian (SAS) AF: 0.00 AC: 0 AN: 82970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51290

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102320

Other (OTH) AF: 0.00 AC: 0 AN: 59504

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with asparagine at codon 131 of the TMEM231 protein (p.Asp131Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TMEM231-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0060
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;.
PhyloP100		6.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.050	N;.;N
REVEL	Benign	0.15
Sift	Benign	0.11	T;.;T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.30
MutPred		0.54		Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);
MVP		0.23
MPC		0.81
ClinPred		0.90	D
GERP RS		5.9
PromoterAI		0.011	Neutral
Varity_R		0.13
gMVP		0.32
Mutation Taster		=86/14	polymorphism

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: rs753709447; hg19: chr16-75589779;