rs115967793

Variant names:

• chr8-93816416-A-G
• rs115967793
• NM_153704.6:c.2952A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_153704.6(TMEM67):​c.2952A>G​(p.Ala984Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000942 in 1,599,276 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (2 hom.)
• Consequence: TMEM67 NM_153704.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.995
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 8-93816416-A-G is Benign according to our data. Variant chr8-93816416-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262749.
• BP7: Synonymous conserved (PhyloP=0.995 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 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.2952A>G	p.Ala984Ala	synonymous	Exon 28 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.2709A>G	p.Ala903Ala	synonymous	Exon 29 of 29	NP_001135773.1
	TMEM67	NR_024522.2		n.2973A>G		non_coding_transcript_exon	Exon 28 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.2952A>G	p.Ala984Ala	synonymous	Exon 28 of 28	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.2835A>G	p.Ala945Ala	synonymous	Exon 27 of 27	ENSP00000388671.2
	TMEM67	ENST00000520680.2	TSL:3	c.3075A>G	p.Ala1025Ala	synonymous	Exon 29 of 29	ENSP00000428785.2

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 623 AN: 152186 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00124 AC: 309 AN: 249808 AF XY: 0.000850

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000610 AC: 882 AN: 1446972 Hom.: 2 Cov.: 25 AF XY: 0.000500 AC XY: 360 AN XY: 720494

African (AFR) AF: 0.0149 AC: 494 AN: 33146

American (AMR) AF: 0.000968 AC: 43 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.00 AC: 0 AN: 85102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00175 AC: 10 AN: 5710

European-Non Finnish (NFE) AF: 0.000250 AC: 275 AN: 1100196

Other (OTH) AF: 0.00100 AC: 60 AN: 59816

GnomAD4 genome AF: 0.00410 AC: 624 AN: 152304 Hom.: 5 Cov.: 33 AF XY: 0.00383 AC XY: 285 AN XY: 74476

African (AFR) AF: 0.0137 AC: 571 AN: 41584

American (AMR) AF: 0.00216 AC: 33 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67994

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00226 Hom.: 0

Bravo AF: 0.00489

Asia WGS AF: 0.000583 AC: 2 AN: 3442

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Joubert syndrome 6 (1)
-	1	-	Meckel syndrome, type 3 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	-	1	Nephronophthisis 11 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.4
DANN	Benign	0.55
PhyloP100		0.99
Mutation Taster		=100/0	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: rs115967793; hg19: chr8-94828644;