16-75540001-A-G

Variant names:

• chr16-75540001-A-G
• rs756652972
• NM_001077418.3:c.944T>C

Variant summary

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

The NM_001077418.3(TMEM231):​c.944T>C​(p.Leu315Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: TMEM231 NM_001077418.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69

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=0.18047541).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.944T>C	p.Leu315Ser	missense_variant	Exon 7 of 7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.1103T>C	p.Leu368Ser	missense_variant	Exon 6 of 6		NP_001070884.2
TMEM231	NR_074083.2	n.1110T>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.944T>C	p.Leu315Ser	missense_variant	Exon 7 of 7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.1031T>C	p.Leu344Ser	missense_variant	Exon 6 of 6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.800T>C	p.Leu267Ser	missense_variant	Exon 6 of 6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.*746T>C		non_coding_transcript_exon_variant	Exon 7 of 7	1		ENSP00000454582.1
TMEM231	ENST00000562410.5	n.*746T>C		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000454582.1
ENSG00000260092	ENST00000460606.1	n.157+2601T>C		intron_variant	Intron 2 of 4	1		ENSP00000457544.1
TMEM231	ENST00000570006.5	n.*324T>C		downstream_gene_variant		5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 FAILED QC

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

GnomAD4 exome Cov.: 31

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.0096	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.00095	T;.;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.21	T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.21
Sift	Uncertain	0.010	D;.;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.30
MutPred		0.34		Gain of disorder (P = 0.046);.;.;
MVP		0.51
MPC		0.027
ClinPred		0.83	D
GERP RS		3.8
Varity_R		0.078
gMVP		0.46

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: rs756652972; hg19: chr16-75573899;