rs3097427

Variant names:

• chr8-93782392-C-T
• rs3097427
• NM_153704.6:c.1066-3C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153704.6(TMEM67):​c.1066-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 1,603,638 control chromosomes in the GnomAD database, including 294,521 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32861 hom., cov: 31)
  • Exomes 𝑓: 0.60 (261660 hom.)
• Consequence: TMEM67 NM_153704.6 splice_region, intron
• Scores: Splicing: ADA: 0.0004581
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.0630
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-93782392-C-T is Benign according to our data. Variant chr8-93782392-C-T is described in ClinVar as Benign. ClinVar VariationId is 96528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

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.1066-3C>T		splice_region intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.823-3C>T		splice_region intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.1087-3C>T		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.1066-3C>T		splice_region intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.1066-3C>T		splice_region intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.427-3831C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98851 AN: 151840 Hom.: 32804 Cov.: 31

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.627

GnomAD2 exomes AF: 0.636 AC: 159161 AN: 250398 AF XY: 0.627

Gnomad AFR exome AF: 0.771

Gnomad AMR exome AF: 0.725

Gnomad ASJ exome AF: 0.628

Gnomad EAS exome AF: 0.836

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.578

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.597 AC: 866613 AN: 1451680 Hom.: 261660 Cov.: 31 AF XY: 0.596 AC XY: 430950 AN XY: 722606

African (AFR) AF: 0.777 AC: 25857 AN: 33274

American (AMR) AF: 0.716 AC: 31966 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 16492 AN: 26044

East Asian (EAS) AF: 0.788 AC: 31233 AN: 39616

South Asian (SAS) AF: 0.612 AC: 52606 AN: 85936

European-Finnish (FIN) AF: 0.576 AC: 30696 AN: 53322

Middle Eastern (MID) AF: 0.604 AC: 3317 AN: 5492

European-Non Finnish (NFE) AF: 0.578 AC: 637801 AN: 1103354

Other (OTH) AF: 0.611 AC: 36645 AN: 60000

GnomAD4 genome AF: 0.651 AC: 98970 AN: 151958 Hom.: 32861 Cov.: 31 AF XY: 0.652 AC XY: 48440 AN XY: 74250

African (AFR) AF: 0.764 AC: 31678 AN: 41446

American (AMR) AF: 0.668 AC: 10193 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2177 AN: 3472

East Asian (EAS) AF: 0.821 AC: 4249 AN: 5176

South Asian (SAS) AF: 0.632 AC: 3045 AN: 4818

European-Finnish (FIN) AF: 0.564 AC: 5930 AN: 10516

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39540 AN: 67958

Other (OTH) AF: 0.632 AC: 1335 AN: 2114

Alfa AF: 0.613 Hom.: 21093

Bravo AF: 0.664

Asia WGS AF: 0.704 AC: 2453 AN: 3478

EpiCase AF: 0.581

EpiControl AF: 0.588

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Joubert syndrome 6 (2)
-	-	2	Meckel syndrome, type 3 (2)
-	-	2	Nephronophthisis 11 (2)
-	-	2	not provided (2)
-	-	1	COACH syndrome 1 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.4
DANN	Benign	0.49
PhyloP100		0.063
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.010		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: rs3097427; hg19: chr8-94794620; COSMIC: COSV60043346; COSMIC: COSV60043346;