NM_153704.6:c.1353delA

Variant names:

• chr8-93786286-GA-G
• rs749435317
• NM_153704.6:c.1353delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_153704.6(TMEM67):​c.1353delA​(p.Glu452LysfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R451R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TMEM67 NM_153704.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.06
• Publications: 1 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-93786286-GA-G is Pathogenic according to our data. Variant chr8-93786286-GA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 225493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1353delA	p.Glu452LysfsTer4	frameshift	Exon 13 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.1110delA	p.Glu371LysfsTer4	frameshift	Exon 14 of 29	NP_001135773.1
	TMEM67	NR_024522.2		n.1374delA		non_coding_transcript_exon	Exon 13 of 29

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.1353delA	p.Glu452LysfsTer4	frameshift	Exon 13 of 28	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.1353delA	p.Glu452LysfsTer4	frameshift	Exon 13 of 27	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.491delA		non_coding_transcript_exon	Exon 4 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251376 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461676 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727156

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111856

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Bardet-Biedl syndrome;C1853153:Joubert syndrome 6;C5435651:COACH syndrome 1 (1)
1	-	-	Joubert syndrome 6 (1)
1	-	-	Meckel syndrome, type 3 (1)
1	-	-	Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 (1)
1	-	-	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs749435317; hg19: chr8-94798514;