8-93755751-CTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTT

Variant names:

• chr8-93755751-C-CTTTT
• rs587779735
• NM_153704.6:c.224-6_224-3dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_153704.6(TMEM67):​c.224-6_224-3dupTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0018 (4 hom.)
  • Failed GnomAD Quality Control
• 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: Uncertain_significance. The variant received 4 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.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.224-6_224-3dupTTTT		splice_acceptor intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+635_-62+638dupTTTT		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.245-6_245-3dupTTTT		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.224-6_224-3dupTTTT		splice_acceptor intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224-6_224-3dupTTTT		splice_acceptor intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244-6_244-3dupTTTT		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000785 AC: 67 AN: 85310 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000412

Gnomad AMI AF: 0.00345

Gnomad AMR AF: 0.000361

Gnomad ASJ AF: 0.00133

Gnomad EAS AF: 0.00130

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000261

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00175 AC: 958 AN: 547376 Hom.: 4 Cov.: 0 AF XY: 0.00184 AC XY: 533 AN XY: 289702

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

African (AFR) AF: 0.00126 AC: 14 AN: 11152

American (AMR) AF: 0.00147 AC: 30 AN: 20398

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 30 AN: 13022

East Asian (EAS) AF: 0.00144 AC: 34 AN: 23592

South Asian (SAS) AF: 0.00478 AC: 203 AN: 42486

European-Finnish (FIN) AF: 0.00113 AC: 37 AN: 32842

Middle Eastern (MID) AF: 0.00139 AC: 3 AN: 2162

European-Non Finnish (NFE) AF: 0.00148 AC: 558 AN: 377170

Other (OTH) AF: 0.00200 AC: 49 AN: 24552

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000785 AC: 67 AN: 85310 Hom.: 0 Cov.: 28 AF XY: 0.000871 AC XY: 35 AN XY: 40162

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

African (AFR) AF: 0.000411 AC: 9 AN: 21894

American (AMR) AF: 0.000360 AC: 3 AN: 8322

Ashkenazi Jewish (ASJ) AF: 0.00133 AC: 3 AN: 2248

East Asian (EAS) AF: 0.00131 AC: 4 AN: 3062

South Asian (SAS) AF: 0.00 AC: 0 AN: 2550

European-Finnish (FIN) AF: 0.000261 AC: 1 AN: 3836

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

European-Non Finnish (NFE) AF: 0.00108 AC: 45 AN: 41518

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), 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;