rs144252983

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001077418.3(TMEM231):​c.582+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000046 in 1,608,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 23)
Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

TMEM231
NM_001077418.3 splice_region, intron

Scores

2
Splicing: ADA: 0.00003145
2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.17

Publications

5 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 16-75545344-G-A is Benign according to our data. Variant chr16-75545344-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2163316.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM231NM_001077418.3 linkc.582+8C>T splice_region_variant, intron_variant Intron 4 of 6 ENST00000258173.11 NP_001070886.1 Q9H6L2-1
TMEM231NM_001077416.2 linkc.741+8C>T splice_region_variant, intron_variant Intron 3 of 5 NP_001070884.2 Q9H6L2
TMEM231NR_074083.2 linkn.748+8C>T splice_region_variant, intron_variant Intron 4 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM231ENST00000258173.11 linkc.582+8C>T splice_region_variant, intron_variant Intron 4 of 6 1 NM_001077418.3 ENSP00000258173.5 Q9H6L2-1
TMEM231ENST00000568377.5 linkc.669+8C>T splice_region_variant, intron_variant Intron 3 of 5 1 ENSP00000476267.1 Q9H6L2-2
TMEM231ENST00000565067.5 linkc.438+482C>T intron_variant Intron 3 of 5 5 ENSP00000457254.1 H3BTN6
ENSG00000260092ENST00000460606.1 linkn.75+8C>T splice_region_variant, intron_variant Intron 1 of 4 1 ENSP00000457544.1 H3BUA1
TMEM231ENST00000562410.5 linkn.*384+8C>T splice_region_variant, intron_variant Intron 4 of 6 1 ENSP00000454582.1 H3BMW7
TMEM231ENST00000570006.5 linkn.544+8C>T splice_region_variant, intron_variant Intron 4 of 6 5 ENSP00000455520.1 H3BPY4

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152090
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000121
AC:
3
AN:
247248
AF XY:
0.00000745
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000501
AC:
73
AN:
1456672
Hom.:
0
Cov.:
31
AF XY:
0.0000553
AC XY:
40
AN XY:
723858
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33256
American (AMR)
AF:
0.00
AC:
0
AN:
44166
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25980
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39568
South Asian (SAS)
AF:
0.0000698
AC:
6
AN:
86004
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53354
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5738
European-Non Finnish (NFE)
AF:
0.0000595
AC:
66
AN:
1108450
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60156
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
Heterozygous variant carriers
0
5
10
15
20
25
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152090
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
74302
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41402
American (AMR)
AF:
0.00
AC:
0
AN:
15254
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4816
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
19
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Benign:1
Nov 30, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
0.27
DANN
Benign
0.37
PhyloP100
-1.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000031
dbscSNV1_RF
Benign
0.0
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

Other links and lift over

dbSNP: rs144252983; hg19: chr16-75579242; API