8-93755751-CTTTTTTTTTTTTT-CTTTTTTTTTTTTTT

Variant names:

• chr8-93755751-C-CT
• rs587779735
• NM_153704.6:c.224-3dupT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BS1_Supporting BS2

The NM_153704.6(TMEM67):​c.224-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 627,798 control chromosomes in the GnomAD database, including 175 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.034 (85 hom., cov: 28)
  • Exomes 𝑓: 0.083 (90 hom.)
• Consequence: TMEM67 NM_153704.6 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 3 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.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0345 (2940/85236) while in subpopulation NFE AF = 0.041 (1700/41476). AF 95% confidence interval is 0.0394. There are 85 homozygotes in GnomAd4. There are 1263 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 85 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.224-3dupT		splice_acceptor intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+638dupT		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.245-3dupT		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.224-3dupT		splice_acceptor intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224-3dupT		splice_acceptor intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244-3dupT		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0345 AC: 2939 AN: 85236 Hom.: 85 Cov.: 28

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.0224

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0347

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.00417

Gnomad MID AF: 0.0317

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0305

GnomAD4 exome AF: 0.0830 AC: 45046 AN: 542562 Hom.: 90 Cov.: 0 AF XY: 0.0858 AC XY: 24609 AN XY: 286824

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

African (AFR) AF: 0.0690 AC: 762 AN: 11048

American (AMR) AF: 0.0714 AC: 1447 AN: 20254

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 1227 AN: 12928

East Asian (EAS) AF: 0.0984 AC: 2291 AN: 23290

South Asian (SAS) AF: 0.131 AC: 5514 AN: 42014

European-Finnish (FIN) AF: 0.0763 AC: 2490 AN: 32642

Middle Eastern (MID) AF: 0.0857 AC: 184 AN: 2146

European-Non Finnish (NFE) AF: 0.0771 AC: 28836 AN: 373938

Other (OTH) AF: 0.0944 AC: 2295 AN: 24302

⚠️ 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: 0.0345 AC: 2940 AN: 85236 Hom.: 85 Cov.: 28 AF XY: 0.0315 AC XY: 1263 AN XY: 40120

African (AFR) AF: 0.0351 AC: 768 AN: 21880

American (AMR) AF: 0.0173 AC: 144 AN: 8312

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 78 AN: 2248

East Asian (EAS) AF: 0.0357 AC: 109 AN: 3056

South Asian (SAS) AF: 0.0282 AC: 72 AN: 2550

European-Finnish (FIN) AF: 0.00417 AC: 16 AN: 3834

Middle Eastern (MID) AF: 0.0339 AC: 4 AN: 118

European-Non Finnish (NFE) AF: 0.0410 AC: 1700 AN: 41476

Other (OTH) AF: 0.0305 AC: 36 AN: 1182

Alfa AF: 0.00901 Hom.: 11

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ciliopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism

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: rs587779735; hg19: chr8-94767979;