NM_153704.6:c.224-12_224-3delTTTTTTTTTT

Variant names:

• chr8-93755751-CTTTTTTTTTT-C
• rs587779735
• NM_153704.6:c.224-12_224-3delTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_153704.6(TMEM67):​c.224-12_224-3delTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000073 in 547,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: TMEM67 NM_153704.6 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 8-93755751-CTTTTTTTTTT-C is Benign according to our data. Variant chr8-93755751-CTTTTTTTTTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3043185.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	NM_153704.6	MANE Select	c.224-12_224-3delTTTTTTTTTT		splice_region intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+629_-62+638delTTTTTTTTTT		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.245-12_245-3delTTTTTTTTTT		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.224-12_224-3delTTTTTTTTTT		splice_region intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224-12_224-3delTTTTTTTTTT		splice_region intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244-12_244-3delTTTTTTTTTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000730 AC: 4 AN: 547778 Hom.: 0 AF XY: 0.00000345 AC XY: 1 AN XY: 289910

African (AFR) AF: 0.000179 AC: 2 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: 0.00 AC: 0 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: 0.00000530 AC: 2 AN: 377420

Other (OTH) AF: 0.00 AC: 0 AN: 24562

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 11

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	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;