chr8-93755775-TA-T

Variant names:

• chr8-93755775-TA-T
• rs386834190
• NM_153704.6:c.224-2delA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Moderate PS3 PP5_Very_Strong

The NM_153704.6(TMEM67):​c.224-2delA variant causes a splice acceptor, intron change. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004569721: RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. PMID:17377820".

• Frequency:
  • Genomes: 𝑓 0.000090 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM67 NM_153704.6 splice_acceptor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.13
• Publications: 1 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, STRONG Submitted by: PanelApp Australia, 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: Ambry Genetics, Orphanet
• 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02978581 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.6, offset of 24, new splice context is: ttcatgtgtatgtctaccAGgat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004569721: RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. PMID: 17377820
• PP5: Variant 8-93755775-TA-T is Pathogenic according to our data. Variant chr8-93755775-TA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 56771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	NM_153704.6	MANE Select	c.224-2delA		splice_acceptor intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+639delA		intron	N/A	NP_001135773.1	Q5HYA8
	TMEM67	NR_024522.2		n.245-2delA		splice_acceptor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.224-2delA		splice_acceptor intron	N/A	ENSP00000389998.3	Q5HYA8
	TMEM67	ENST00000452276.6	TSL:1	c.224-2delA		splice_acceptor intron	N/A	ENSP00000388671.2	C9JRQ8
	TMEM67	ENST00000474944.5	TSL:1	n.244-2delA		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000900 AC: 13 AN: 144458 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000297

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000410 AC: 466 AN: 1136608 Hom.: 0 Cov.: 8 AF XY: 0.000421 AC XY: 242 AN XY: 574986

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

African (AFR) AF: 0.000888 AC: 21 AN: 23642

American (AMR) AF: 0.0000618 AC: 2 AN: 32340

Ashkenazi Jewish (ASJ) AF: 0.0000443 AC: 1 AN: 22548

East Asian (EAS) AF: 0.0000551 AC: 2 AN: 36294

South Asian (SAS) AF: 0.000128 AC: 9 AN: 70128

European-Finnish (FIN) AF: 0.0000403 AC: 2 AN: 49656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4184

European-Non Finnish (NFE) AF: 0.000479 AC: 407 AN: 849450

Other (OTH) AF: 0.000455 AC: 22 AN: 48366

⚠️ 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: 0.0000899 AC: 13 AN: 144550 Hom.: 0 Cov.: 0 AF XY: 0.000142 AC XY: 10 AN XY: 70388

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

African (AFR) AF: 0.000296 AC: 11 AN: 37208

American (AMR) AF: 0.00 AC: 0 AN: 13940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5000

South Asian (SAS) AF: 0.00 AC: 0 AN: 4718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67286

Other (OTH) AF: 0.00 AC: 0 AN: 2002

⚠️ 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: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Joubert syndrome 6;C1865794:RHYNS syndrome;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 (1)
1	-	-	Meckel syndrome, type 3 (1)
1	-	-	Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 (1)
1	-	-	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: 27
DS_AL_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: rs386834190; hg19: chr8-94768003; COSMIC: COSV60035525;