8-93755751-CTTTTTTTTTTTTT-CTT

Variant names:

• chr8-93755751-CTTTTTTTTTTT-C
• rs587779735
• NM_153704.6:c.224-13_224-3delTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_153704.6(TMEM67):​c.224-13_224-3delTTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000442 in 633,118 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000023 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: TMEM67 NM_153704.6 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.28
• 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, 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 8-93755751-CTTTTTTTTTTT-C is Benign according to our data. Variant chr8-93755751-CTTTTTTTTTTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1905774.Status of the report is criteria_provided_single_submitter, 1 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.224-13_224-3delTTTTTTTTTTT		splice_region intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+628_-62+638delTTTTTTTTTTT		intron	N/A	NP_001135773.1	Q5HYA8
	TMEM67	NR_024522.2		n.245-13_245-3delTTTTTTTTTTT		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.224-26_224-16delTTTTTTTTTTT		intron	N/A	ENSP00000389998.3	Q5HYA8
	TMEM67	ENST00000452276.6	TSL:1	c.224-26_224-16delTTTTTTTTTTT		intron	N/A	ENSP00000388671.2	C9JRQ8
	TMEM67	ENST00000474944.5	TSL:1	n.244-26_244-16delTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000234 AC: 2 AN: 85340 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000475 AC: 26 AN: 547778 Hom.: 0 AF XY: 0.0000586 AC XY: 17 AN XY: 289910

African (AFR) AF: 0.00 AC: 0 AN: 11158

American (AMR) AF: 0.00 AC: 0 AN: 20424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13028

East Asian (EAS) AF: 0.0000423 AC: 1 AN: 23616

South Asian (SAS) AF: 0.00 AC: 0 AN: 42544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2162

European-Non Finnish (NFE) AF: 0.0000556 AC: 21 AN: 377418

Other (OTH) AF: 0.000163 AC: 4 AN: 24564

GnomAD4 genome AF: 0.0000234 AC: 2 AN: 85340 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 40174

African (AFR) AF: 0.00 AC: 0 AN: 21898

American (AMR) AF: 0.000240 AC: 2 AN: 8322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2250

East Asian (EAS) AF: 0.00 AC: 0 AN: 3062

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: 0.00 AC: 0 AN: 41540

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

Alfa AF: 0.00 Hom.: 11

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	TMEM67-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

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;