8-93770503-G-A

Variant names:

• chr8-93770503-G-A
• rs3097418
• NM_153704.6:c.652-2086G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153704.6(TMEM67):​c.652-2086G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,034 control chromosomes in the GnomAD database, including 5,137 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5137 hom., cov: 32)
• Consequence: TMEM67 NM_153704.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890
• 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 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.323 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.652-2086G>A		intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.409-2086G>A		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.673-2086G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.652-2086G>A		intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.652-2086G>A		intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.426+11927G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38729 AN: 151916 Hom.: 5124 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.256

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.255 AC: 38773 AN: 152034 Hom.: 5137 Cov.: 32 AF XY: 0.256 AC XY: 18996 AN XY: 74312

African (AFR) AF: 0.194 AC: 8054 AN: 41478

American (AMR) AF: 0.234 AC: 3581 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 990 AN: 3470

East Asian (EAS) AF: 0.324 AC: 1675 AN: 5168

South Asian (SAS) AF: 0.337 AC: 1625 AN: 4820

European-Finnish (FIN) AF: 0.246 AC: 2599 AN: 10558

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19270 AN: 67956

Other (OTH) AF: 0.263 AC: 554 AN: 2108

Alfa AF: 0.276 Hom.: 4837

Bravo AF: 0.250

Asia WGS AF: 0.283 AC: 989 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.7
DANN	Benign	0.67
PhyloP100		0.089
Mutation Taster		=100/0	polymorphism (auto)

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: rs3097418; hg19: chr8-94782731;