16-75540029-G-A

Position:

• chr16-75540029-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001077418.3(TMEM231):​c.916C>T​(p.Pro306Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM231 NM_001077418.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.193

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13017598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.916C>T	p.Pro306Ser	missense_variant	7/7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.1075C>T	p.Pro359Ser	missense_variant	6/6		NP_001070884.2
TMEM231	NR_074083.2	n.1082C>T		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.916C>T	p.Pro306Ser	missense_variant	7/7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.1003C>T	p.Pro335Ser	missense_variant	6/6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.772C>T	p.Pro258Ser	missense_variant	6/6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.*718C>T		non_coding_transcript_exon_variant	7/7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.*296C>T		non_coding_transcript_exon_variant	7/7	5		ENSP00000455520.1
TMEM231	ENST00000562410.5	n.*718C>T		3_prime_UTR_variant	7/7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.*296C>T		3_prime_UTR_variant	7/7	5		ENSP00000455520.1
ENSG00000260092	ENST00000460606.1	n.157+2573C>T		intron_variant		1		ENSP00000457544.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461090 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.7
DANN	Benign	0.61
DEOGEN2	Benign	0.0024	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.40	N;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N;.;N
REVEL	Benign	0.098
Sift	Benign	0.30	T;.;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.058
MutPred		0.67		Loss of glycosylation at T303 (P = 0.0472);.;.;
MVP		0.13
MPC		0.0085
ClinPred		0.055	T
GERP RS		-0.57
Varity_R		0.037
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-75573927;