chr8-93755751-C-CTTTTT

Variant names:

• chr8-93755751-C-CTTTTT
• rs587779735
• NM_153704.6:c.224-7_224-3dupTTTTT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_153704.6(TMEM67):​c.224-7_224-3dupTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 632,934 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: TMEM67 NM_153704.6 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.723
• Publications: 0 publications found

Genes affected

TMEM67 (HGNC:28396): (transmembrane protein 67) The protein encoded by this gene localizes to the primary cilium and to the plasma membrane. The gene functions in centriole migration to the apical membrane and formation of the primary cilium. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Meckel syndrome type 3 (MKS3) and Joubert syndrome type 6 (JBTS6). [provided by RefSeq, Nov 2008]

TMEM67 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• COACH syndrome 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Meckel syndrome, type 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• nephronophthisis 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• COACH syndrome 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Joubert syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Boichis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153704.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	NM_153704.6	MANE Select	c.224-7_224-3dupTTTTT		splice_acceptor intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+634_-62+638dupTTTTT		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.245-7_245-3dupTTTTT		splice_acceptor intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.224-7_224-3dupTTTTT		splice_acceptor intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224-7_224-3dupTTTTT		splice_acceptor intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244-7_244-3dupTTTTT		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000141 AC: 12 AN: 85332 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000457

Gnomad AMI AF: 0.00172

Gnomad AMR AF: 0.000120

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: 0.000217

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000654 AC: 358 AN: 547602 Hom.: 0 Cov.: 0 AF XY: 0.000659 AC XY: 191 AN XY: 289820

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000269 AC: 3 AN: 11156

American (AMR) AF: 0.000490 AC: 10 AN: 20414

Ashkenazi Jewish (ASJ) AF: 0.000921 AC: 12 AN: 13024

East Asian (EAS) AF: 0.000678 AC: 16 AN: 23610

South Asian (SAS) AF: 0.00183 AC: 78 AN: 42520

European-Finnish (FIN) AF: 0.000457 AC: 15 AN: 32858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2160

European-Non Finnish (NFE) AF: 0.000559 AC: 211 AN: 377312

Other (OTH) AF: 0.000530 AC: 13 AN: 24548

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000141 AC: 12 AN: 85332 Hom.: 0 Cov.: 28 AF XY: 0.000124 AC XY: 5 AN XY: 40168

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000457 AC: 1 AN: 21894

American (AMR) AF: 0.000120 AC: 1 AN: 8322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2248

East Asian (EAS) AF: 0.00 AC: 0 AN: 3060

South Asian (SAS) AF: 0.00 AC: 0 AN: 2552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 118

European-Non Finnish (NFE) AF: 0.000217 AC: 9 AN: 41540

Other (OTH) AF: 0.00 AC: 0 AN: 1182

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000824244), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.72

Splicing

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

Other links and lift over

dbSNP: rs587779735; hg19: chr8-94767979;