rs115563233

Variant names:

• chr8-93799758-G-A
• rs115563233
• NM_153704.6:c.2241G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_153704.6(TMEM67):​c.2241G>A​(p.Gln747Gln) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,612,412 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (13 hom.)
• Consequence: TMEM67 NM_153704.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.9765
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7 O:1
• Conservation: PhyloP100: 3.42
• Publications: 3 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 -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 8-93799758-G-A is Benign according to our data. Variant chr8-93799758-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242363.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

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.2241G>A	p.Gln747Gln	splice_region synonymous	Exon 21 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.1998G>A	p.Gln666Gln	splice_region synonymous	Exon 22 of 29	NP_001135773.1	Q5HYA8
	TMEM67	NR_024522.2		n.2262G>A		splice_region non_coding_transcript_exon	Exon 21 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.2241G>A	p.Gln747Gln	splice_region synonymous	Exon 21 of 28	ENSP00000389998.3	Q5HYA8
	TMEM67	ENST00000452276.6	TSL:1	c.2241G>A	p.Gln747Gln	splice_region synonymous	Exon 21 of 27	ENSP00000388671.2	C9JRQ8
	TMEM67	ENST00000474944.5	TSL:1	n.1379G>A		splice_region non_coding_transcript_exon	Exon 12 of 17

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 151974 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00520

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00186 AC: 467 AN: 251196 AF XY: 0.00217

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00204 AC: 2980 AN: 1460322 Hom.: 13 Cov.: 30 AF XY: 0.00217 AC XY: 1580 AN XY: 726554

African (AFR) AF: 0.000239 AC: 8 AN: 33448

American (AMR) AF: 0.00130 AC: 58 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00583 AC: 503 AN: 86228

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53252

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5762

European-Non Finnish (NFE) AF: 0.00200 AC: 2227 AN: 1110780

Other (OTH) AF: 0.00215 AC: 130 AN: 60352

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152090 Hom.: 0 Cov.: 31 AF XY: 0.00149 AC XY: 111 AN XY: 74344

African (AFR) AF: 0.000410 AC: 17 AN: 41494

American (AMR) AF: 0.00131 AC: 20 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00520 AC: 25 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 67982

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00182 Hom.: 3

Bravo AF: 0.00144

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00267

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Joubert syndrome 6 (1)
-	1	-	Kidney disorder (1)
-	-	1	Meckel syndrome, type 3 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	Nephronophthisis 11 (1)
-	-	1	not specified (1)
-	-	1	TMEM67-related disorder (1)
-	-	-	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Benign	0.90
PhyloP100		3.4
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.80		Position offset: 16
DS_DL_spliceai		0.24		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs115563233; hg19: chr8-94811986;