8-93755751-CTTTTTTTTTTTTT-CTTTTTTTTT

Variant names:

• chr8-93755751-CTTTT-C
• rs587779735
• NM_153704.6:c.224-6_224-3delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_153704.6(TMEM67):​c.224-6_224-3delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 631,672 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0020 (0 hom.)
• Consequence: TMEM67 NM_153704.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.727
• 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 0 ACMG points.

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.224-6_224-3delTTTT		splice_region intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+635_-62+638delTTTT		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.245-6_245-3delTTTT		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.224-6_224-3delTTTT		splice_region intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224-6_224-3delTTTT		splice_region intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244-6_244-3delTTTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000246 AC: 21 AN: 85340 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000361

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000651

Gnomad SAS AF: 0.000389

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000289

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00201 AC: 1097 AN: 546332 Hom.: 0 AF XY: 0.00183 AC XY: 530 AN XY: 289156

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

African (AFR) AF: 0.00270 AC: 30 AN: 11114

American (AMR) AF: 0.0156 AC: 316 AN: 20270

Ashkenazi Jewish (ASJ) AF: 0.00139 AC: 18 AN: 12990

East Asian (EAS) AF: 0.0101 AC: 237 AN: 23460

South Asian (SAS) AF: 0.000659 AC: 28 AN: 42468

European-Finnish (FIN) AF: 0.00143 AC: 47 AN: 32784

Middle Eastern (MID) AF: 0.000463 AC: 1 AN: 2162

European-Non Finnish (NFE) AF: 0.000911 AC: 343 AN: 376606

Other (OTH) AF: 0.00315 AC: 77 AN: 24478

⚠️ 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: 0.000246 AC: 21 AN: 85340 Hom.: 0 Cov.: 28 AF XY: 0.000299 AC XY: 12 AN XY: 40174

African (AFR) AF: 0.000137 AC: 3 AN: 21898

American (AMR) AF: 0.000360 AC: 3 AN: 8322

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

East Asian (EAS) AF: 0.000653 AC: 2 AN: 3062

South Asian (SAS) AF: 0.000392 AC: 1 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: 0.000289 AC: 12 AN: 41540

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

Alfa AF: 0.00 Hom.: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73
Mutation Taster		=99/1	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;