16-75545349-T-G

Variant names:

• chr16-75545349-T-G
• rs114290622
• NM_001077418.3:c.582+3A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001077418.3(TMEM231):​c.582+3A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,380 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 predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM231 NM_001077418.3 splice_region, intron
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• Publications: 0 publications found

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

ENSG00000260092 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.582+3A>C		splice_region_variant, intron_variant	Intron 4 of 6	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.741+3A>C		splice_region_variant, intron_variant	Intron 3 of 5		NP_001070884.2
TMEM231	NR_074083.2	n.748+3A>C		splice_region_variant, intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.582+3A>C		splice_region_variant, intron_variant	Intron 4 of 6	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.669+3A>C		splice_region_variant, intron_variant	Intron 3 of 5	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.438+477A>C		intron_variant	Intron 3 of 5	5		ENSP00000457254.1
ENSG00000260092	ENST00000460606.1	n.75+3A>C		splice_region_variant, intron_variant	Intron 1 of 4	1		ENSP00000457544.1
TMEM231	ENST00000562410.5	n.*384+3A>C		splice_region_variant, intron_variant	Intron 4 of 6	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.544+3A>C		splice_region_variant, intron_variant	Intron 4 of 6	5		ENSP00000455520.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460380 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726254

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110904

Other (OTH) AF: 0.0000166 AC: 1 AN: 60320

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.33
DANN	Benign	0.72
PhyloP100		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 3

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

Other links and lift over

dbSNP: rs114290622; hg19: chr16-75579247;