8-93755751-CTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTT

Variant names:

• chr8-93755751-C-CTTT
• rs587779735
• NM_153704.6:c.224-5_224-3dupTTT

Variant summary

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

The NM_153704.6(TMEM67):​c.224-5_224-3dupTTT 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 0.0017 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0042 (13 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 13 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.224-5_224-3dupTTT		splice_acceptor intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+636_-62+638dupTTT		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.245-5_245-3dupTTT		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.224-5_224-3dupTTT		splice_acceptor intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224-5_224-3dupTTT		splice_acceptor intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244-5_244-3dupTTT		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 148 AN: 85292 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00692

Gnomad AMR AF: 0.000842

Gnomad ASJ AF: 0.00222

Gnomad EAS AF: 0.00163

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000521

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.000849

GnomAD4 exome AF: 0.00416 AC: 2276 AN: 546700 Hom.: 13 Cov.: 0 AF XY: 0.00443 AC XY: 1283 AN XY: 289328

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

African (AFR) AF: 0.00296 AC: 33 AN: 11150

American (AMR) AF: 0.00427 AC: 87 AN: 20394

Ashkenazi Jewish (ASJ) AF: 0.00446 AC: 58 AN: 13010

East Asian (EAS) AF: 0.00318 AC: 75 AN: 23568

South Asian (SAS) AF: 0.0124 AC: 527 AN: 42358

European-Finnish (FIN) AF: 0.00323 AC: 106 AN: 32810

Middle Eastern (MID) AF: 0.00371 AC: 8 AN: 2154

European-Non Finnish (NFE) AF: 0.00343 AC: 1294 AN: 376736

Other (OTH) AF: 0.00359 AC: 88 AN: 24520

⚠️ 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: 0.00174 AC: 148 AN: 85292 Hom.: 0 Cov.: 28 AF XY: 0.00164 AC XY: 66 AN XY: 40158

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

African (AFR) AF: 0.00123 AC: 27 AN: 21892

American (AMR) AF: 0.000841 AC: 7 AN: 8320

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 5 AN: 2248

East Asian (EAS) AF: 0.00163 AC: 5 AN: 3060

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

European-Finnish (FIN) AF: 0.000521 AC: 2 AN: 3836

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

European-Non Finnish (NFE) AF: 0.00234 AC: 97 AN: 41510

Other (OTH) AF: 0.000847 AC: 1 AN: 1180

⚠️ 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.

Alfa AF: 0.00142 Hom.: 11

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;