8-93755751-CTTTTTTTTTTTTT-CTTTTT

Variant names:

• chr8-93755751-CTTTTTTTT-C
• rs587779735
• NM_153704.6:c.224-10_224-3delTTTTTTTT

Variant summary

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

The NM_153704.6(TMEM67):​c.224-10_224-3delTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 633,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000069 (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-CTTTTTTTT-C is Benign according to our data. Variant chr8-93755751-CTTTTTTTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3352454.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.224-10_224-3delTTTTTTTT		splice_region intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+631_-62+638delTTTTTTTT		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.245-10_245-3delTTTTTTTT		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.224-10_224-3delTTTTTTTT		splice_region intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224-10_224-3delTTTTTTTT		splice_region intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244-10_244-3delTTTTTTTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000469 AC: 4 AN: 85340 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000120

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: 0.0000481

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000694 AC: 38 AN: 547774 Hom.: 0 AF XY: 0.0000586 AC XY: 17 AN XY: 289906

African (AFR) AF: 0.000179 AC: 2 AN: 11158

American (AMR) AF: 0.000245 AC: 5 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: 0.0000235 AC: 1 AN: 42542

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: 0.0000715 AC: 27 AN: 377416

Other (OTH) AF: 0.000122 AC: 3 AN: 24564

GnomAD4 genome AF: 0.0000469 AC: 4 AN: 85340 Hom.: 0 Cov.: 28 AF XY: 0.0000249 AC XY: 1 AN XY: 40174

African (AFR) AF: 0.0000457 AC: 1 AN: 21870

American (AMR) AF: 0.000120 AC: 1 AN: 8312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3072

South Asian (SAS) AF: 0.00 AC: 0 AN: 2568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 126

European-Non Finnish (NFE) AF: 0.0000481 AC: 2 AN: 41546

Other (OTH) AF: 0.00 AC: 0 AN: 1180

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;