16-75545464-G-A

Position:

chr16-75545464-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_001077418.3(TMEM231):c.470C>T(p.Ala157Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,588,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 21)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.64

Variant links:

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 links:

ENSG00000259992 (HGNC:):

ENSG00000259992 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.014824361).

BP6

Variant 16-75545464-G-A is Benign according to our data. Variant chr16-75545464-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 540545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00164 (239/145540) while in subpopulation AFR AF= 0.0057 (222/38974). AF 95% confidence interval is 0.00508. There are 0 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM231	NM_001077418.3 link	c.470C>T	p.Ala157Val	missense_variant	4/7	ENST00000258173.11	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2 link	c.629C>T	p.Ala210Val	missense_variant	3/6		NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2 link	n.636C>T		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM231	ENST00000258173.11 link	c.470C>T	p.Ala157Val	missense_variant	4/7	1	NM_001077418.3	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000568377.5 link	c.557C>T	p.Ala186Val	missense_variant	3/6	1		ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000565067.5 link	c.438+362C>T		intron_variant		5		ENSP00000457254.1	H3BTN6
TMEM231	ENST00000562410.5 link	n.*272C>T		non_coding_transcript_exon_variant	4/7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.432C>T		non_coding_transcript_exon_variant	4/7	5		ENSP00000455520.1	H3BPY4
TMEM231	ENST00000562410.5 link	n.*272C>T		3_prime_UTR_variant	4/7	1		ENSP00000454582.1	H3BMW7
ENSG00000260092	ENST00000460606.1 link	n.-38C>T		upstream_gene_variant		1		ENSP00000457544.1	H3BUA1

Frequencies

GnomAD3 genomes

AF:

0.00165

AC:

240

AN:

145426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00574

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000491

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:

0.000120

Gnomad OTH

AF:

0.00103

GnomAD3 exomes

AF:

0.000558

AC:

136

AN:

243772

Hom.:

AF XY:

0.000468

AC XY:

AN XY:

132506

show subpopulations

Gnomad AFR exome

AF:

0.00665

Gnomad AMR exome

AF:

0.000480

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.000682

GnomAD4 exome

AF:

0.000288

AC:

415

AN:

1443342

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

193

AN XY:

716634

show subpopulations

Gnomad4 AFR exome

AF:

0.00743

Gnomad4 AMR exome

AF:

0.000530

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000468

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000902

Gnomad4 OTH exome

AF:

0.000655

GnomAD4 genome

AF:

0.00164

AC:

239

AN:

145540

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

105

AN XY:

70562

show subpopulations

Gnomad4 AFR

AF:

0.00570

Gnomad4 AMR

AF:

0.000491

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000120

Gnomad4 OTH

AF:

0.00102

Alfa

AF:

0.000761

Hom.:

Bravo

AF:

0.00222

ESP6500AA

AF:

0.00520

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000663

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.015

T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.1

D;.

REVEL

Uncertain

0.44

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.054

T;T

Polyphen

1.0

D;.

Vest4

0.63

MVP

0.42

MPC

3.2

ClinPred

0.013

GERP RS

4.2

Varity_R

0.34

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over