rs199605221

Variant names:

• chr16-75540154-T-G
• rs199605221
• NM_001077418.3:c.791A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_001077418.3(TMEM231):​c.791A>C​(p.Glu264Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000974 in 1,613,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: TMEM231 NM_001077418.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.45

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]

ENSG00000260092 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.001 (1468/1460974) while in subpopulation NFE AF= 0.00119 (1324/1111542). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4_exome. There are 724 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.791A>C	p.Glu264Ala	missense_variant	Exon 7 of 7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.950A>C	p.Glu317Ala	missense_variant	Exon 6 of 6		NP_001070884.2
TMEM231	NR_074083.2	n.957A>C		non_coding_transcript_exon_variant	Exon 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.791A>C	p.Glu264Ala	missense_variant	Exon 7 of 7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.878A>C	p.Glu293Ala	missense_variant	Exon 6 of 6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.647A>C	p.Glu216Ala	missense_variant	Exon 6 of 6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.*593A>C		non_coding_transcript_exon_variant	Exon 7 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.*171A>C		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000455520.1
TMEM231	ENST00000562410.5	n.*593A>C		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.*171A>C		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000455520.1
ENSG00000260092	ENST00000460606.1	n.157+2448A>C		intron_variant	Intron 2 of 4	1		ENSP00000457544.1

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000525 AC: 130 AN: 247402 Hom.: 0 AF XY: 0.000506 AC XY: 68 AN XY: 134350

Gnomad AFR exome AF: 0.000648

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000822

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.00100 AC: 1468 AN: 1460974 Hom.: 0 Cov.: 32 AF XY: 0.000996 AC XY: 724 AN XY: 726778

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.000881

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000938

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000806 AC XY: 60 AN XY: 74462

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000846 Hom.: 0

Bravo AF: 0.000759

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.000847 AC: 7

ExAC AF: 0.000438 AC: 53

EpiCase AF: 0.000545

EpiControl AF: 0.000712

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 317 of the TMEM231 protein (p.Glu317Ala). This variant is present in population databases (rs199605221, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TMEM231-related conditions. ClinVar contains an entry for this variant (Variation ID: 286672). 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: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). 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. -

not provided Uncertain:2

Dec 10, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Mar 22, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Mar 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.878A>C (p.E293A) alteration is located in exon 6 (coding exon 6) of the TMEM231 gene. This alteration results from a A to C substitution at nucleotide position 878, causing the glutamic acid (E) at amino acid position 293 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.2	D;.;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.012	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.88
MVP		0.56
MPC		0.047
ClinPred		0.072	T
GERP RS		4.3
Varity_R		0.46
gMVP		0.83

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: rs199605221; hg19: chr16-75574052;