16-75556215-C-T

Variant names:

• chr16-75556215-C-T
• rs3743602
• NM_001077418.3:c.-6G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001077418.3(TMEM231):​c.-6G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000237 in 1,264,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: TMEM231 NM_001077418.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.182
• Publications: 12 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Meckel syndrome, type 11

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• 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

ENSG00000259992 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077418.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	NM_001077418.3	MANE Select	c.-6G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001070886.1	Q9H6L2-1
	TMEM231	NM_001077418.3	MANE Select	c.-6G>A		5_prime_UTR	Exon 1 of 7	NP_001070886.1	Q9H6L2-1
	TMEM231	NM_001077416.2		c.57G>A	p.Arg19Arg	synonymous	Exon 1 of 6	NP_001070884.2	Q9H6L2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.-6G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000258173.5	Q9H6L2-1
	TMEM231	ENST00000568377.5	TSL:1	c.-16G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000476267.1	Q9H6L2-2
	TMEM231	ENST00000565067.5	TSL:5	c.-6G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000457254.1	H3BTN6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000183 AC: 1 AN: 54578 AF XY: 0.00

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: 0.0000316

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000237 AC: 3 AN: 1264516 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 613856

African (AFR) AF: 0.00 AC: 0 AN: 25306

American (AMR) AF: 0.0000571 AC: 1 AN: 17516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18162

East Asian (EAS) AF: 0.00 AC: 0 AN: 30306

South Asian (SAS) AF: 0.00 AC: 0 AN: 60666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5100

European-Non Finnish (NFE) AF: 0.00000195 AC: 2 AN: 1023128

Other (OTH) AF: 0.00 AC: 0 AN: 52514

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.4
DANN	Benign	0.93
PhyloP100		-0.18
PromoterAI		-0.17	Neutral

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

Other links and lift over

dbSNP: rs3743602; hg19: chr16-75590113;