16-75556119-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001077418.3(TMEM231):c.91G>A(p.Ala31Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,573,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: TMEM231 NM_001077418.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.00500

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00313285).
• BP6: Variant 16-75556119-C-T is Benign according to our data. Variant chr16-75556119-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284419.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00181 (276/152368) while in subpopulation AFR AF= 0.00623 (259/41592). AF 95% confidence interval is 0.0056. There are 0 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM231	NM_001077418.3	c.91G>A	p.Ala31Thr	missense_variant	1/7	ENST00000258173.11
TMEM231	NM_001077416.2	c.153G>A	p.Pro51=	synonymous_variant	1/6
TMEM231	NR_074083.2	n.134G>A		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM231	ENST00000258173.11	c.91G>A	p.Ala31Thr	missense_variant	1/7	1	NM_001077418.3	P1

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 276 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000365 AC: 65 AN: 178310 Hom.: 0 AF XY: 0.000336 AC XY: 33 AN XY: 98340

Gnomad AFR exome AF: 0.00631

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 211 AN: 1421176 Hom.: 0 Cov.: 30 AF XY: 0.000119 AC XY: 84 AN XY: 703684

Gnomad4 AFR exome AF: 0.00540

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000366

Gnomad4 OTH exome AF: 0.000340

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.00187 AC XY: 139 AN XY: 74504

Gnomad4 AFR AF: 0.00623

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.00184

ESP6500AA AF: 0.00303 AC: 12

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000498 AC: 59

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 17, 2016	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.051	T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N
PROVEAN	Benign	0.39	N;N
REVEL	Benign	0.053
Sift	Benign	0.30	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.0010	B;.
Vest4		0.072
MVP		0.22
ClinPred		0.041	T
GERP RS		0.53
Varity_R		0.043
gMVP		0.44

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: rs202215735; hg19: chr16-75590017;