chr8-93785424-C-T

Variant names:

• chr8-93785424-C-T
• rs73694952
• NM_153704.6:c.1288+46C>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.1288+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,566,892 control chromosomes in the GnomAD database, including 1,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (652 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (595 hom.)
• Consequence: TMEM67 NM_153704.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.180
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-93785424-C-T is Benign according to our data. Variant chr8-93785424-C-T is described in ClinVar as Benign. ClinVar VariationId is 126298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 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.1288+46C>T		intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.1045+46C>T		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.1309+46C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.1288+46C>T		intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.1288+46C>T		intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.427-799C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0512 AC: 7789 AN: 152008 Hom.: 648 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.0441

GnomAD2 exomes AF: 0.0139 AC: 3440 AN: 247430 AF XY: 0.0103

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.000502

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000494

Gnomad NFE exome AF: 0.000877

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00559 AC: 7915 AN: 1414766 Hom.: 595 Cov.: 24 AF XY: 0.00494 AC XY: 3493 AN XY: 706620

African (AFR) AF: 0.183 AC: 5903 AN: 32210

American (AMR) AF: 0.0121 AC: 536 AN: 44274

Ashkenazi Jewish (ASJ) AF: 0.000776 AC: 20 AN: 25774

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39296

South Asian (SAS) AF: 0.000638 AC: 54 AN: 84668

European-Finnish (FIN) AF: 0.0000388 AC: 2 AN: 51516

Middle Eastern (MID) AF: 0.0176 AC: 100 AN: 5670

European-Non Finnish (NFE) AF: 0.000452 AC: 485 AN: 1072616

Other (OTH) AF: 0.0139 AC: 814 AN: 58742

GnomAD4 genome AF: 0.0514 AC: 7826 AN: 152126 Hom.: 652 Cov.: 32 AF XY: 0.0500 AC XY: 3718 AN XY: 74358

African (AFR) AF: 0.175 AC: 7275 AN: 41466

American (AMR) AF: 0.0240 AC: 367 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68016

Other (OTH) AF: 0.0437 AC: 92 AN: 2106

Alfa AF: 0.0127 Hom.: 52

Bravo AF: 0.0595

Asia WGS AF: 0.0110 AC: 39 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.0
DANN	Benign	0.48
PhyloP100		-0.18
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: rs73694952; hg19: chr8-94797652;