8-93755751-CTTTTTTTTTTTTT-CTTTTTTTTTTTT

Variant names:

• chr8-93755751-CT-C
• rs587779735
• NM_153704.6:c.224-3delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_153704.6(TMEM67):​c.224-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 623,164 control chromosomes in the GnomAD database, including 231 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (221 hom., cov: 28)
  • Exomes 𝑓: 0.14 (10 hom.)
• Consequence: TMEM67 NM_153704.6 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.723
• 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 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.224-3delT		splice_region intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+638delT		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.245-3delT		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.224-3delT		splice_region intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224-3delT		splice_region intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244-3delT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0610 AC: 5203 AN: 85360 Hom.: 221 Cov.: 28

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.00172

Gnomad AMR AF: 0.0363

Gnomad ASJ AF: 0.0125

Gnomad EAS AF: 0.00846

Gnomad SAS AF: 0.00623

Gnomad FIN AF: 0.000782

Gnomad MID AF: 0.0317

Gnomad NFE AF: 0.00780

Gnomad OTH AF: 0.0593

GnomAD4 exome AF: 0.144 AC: 77177 AN: 537804 Hom.: 10 Cov.: 0 AF XY: 0.148 AC XY: 41917 AN XY: 284090

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.208 AC: 2284 AN: 10986

American (AMR) AF: 0.112 AC: 2243 AN: 20096

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 2170 AN: 12828

East Asian (EAS) AF: 0.209 AC: 4813 AN: 23042

South Asian (SAS) AF: 0.109 AC: 4505 AN: 41416

European-Finnish (FIN) AF: 0.140 AC: 4532 AN: 32372

Middle Eastern (MID) AF: 0.164 AC: 349 AN: 2126

European-Non Finnish (NFE) AF: 0.140 AC: 51914 AN: 370860

Other (OTH) AF: 0.181 AC: 4367 AN: 24078

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0610 AC: 5204 AN: 85360 Hom.: 221 Cov.: 28 AF XY: 0.0602 AC XY: 2421 AN XY: 40188

African (AFR) AF: 0.202 AC: 4432 AN: 21916

American (AMR) AF: 0.0363 AC: 302 AN: 8324

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 28 AN: 2248

East Asian (EAS) AF: 0.00816 AC: 25 AN: 3062

South Asian (SAS) AF: 0.00627 AC: 16 AN: 2552

European-Finnish (FIN) AF: 0.000782 AC: 3 AN: 3836

Middle Eastern (MID) AF: 0.0254 AC: 3 AN: 118

European-Non Finnish (NFE) AF: 0.00780 AC: 324 AN: 41542

Other (OTH) AF: 0.0592 AC: 70 AN: 1182

Alfa AF: 0.00 Hom.: 11

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Nephronophthisis 11 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.72
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: rs587779735; hg19: chr8-94767979;