8-93755751-CTTTTTTTTTTTTT-CTTTTTTTTTT

Variant names:

• chr8-93755751-CTTT-C
• rs587779735
• NM_153704.6:c.224-5_224-3delTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_153704.6(TMEM67):​c.224-5_224-3delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00901 in 628,078 control chromosomes in the GnomAD database, including 30 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (27 hom., cov: 28)
  • Exomes 𝑓: 0.0086 (3 hom.)
• Consequence: TMEM67 NM_153704.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.727
• 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.

• BP6: Variant 8-93755751-CTTT-C is Benign according to our data. Variant chr8-93755751-CTTT-C is described in ClinVar as Benign. ClinVar VariationId is 281166.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0777 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.224-5_224-3delTTT		splice_region intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+636_-62+638delTTT		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.245-5_245-3delTTT		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.224-5_224-3delTTT		splice_region intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224-5_224-3delTTT		splice_region intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244-5_244-3delTTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1002 AN: 85298 Hom.: 27 Cov.: 28

Gnomad AFR AF: 0.00247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0830

Gnomad ASJ AF: 0.00178

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.00312

Gnomad FIN AF: 0.00626

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0203

GnomAD4 exome AF: 0.00859 AC: 4661 AN: 542780 Hom.: 3 AF XY: 0.00802 AC XY: 2304 AN XY: 287200

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

African (AFR) AF: 0.0169 AC: 187 AN: 11034

American (AMR) AF: 0.0464 AC: 931 AN: 20074

Ashkenazi Jewish (ASJ) AF: 0.00728 AC: 94 AN: 12906

East Asian (EAS) AF: 0.0341 AC: 790 AN: 23152

South Asian (SAS) AF: 0.00360 AC: 152 AN: 42234

European-Finnish (FIN) AF: 0.00807 AC: 263 AN: 32580

Middle Eastern (MID) AF: 0.00651 AC: 14 AN: 2150

European-Non Finnish (NFE) AF: 0.00522 AC: 1953 AN: 374386

Other (OTH) AF: 0.0114 AC: 277 AN: 24264

⚠️ 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: 0.0117 AC: 1000 AN: 85298 Hom.: 27 Cov.: 28 AF XY: 0.0137 AC XY: 549 AN XY: 40148

African (AFR) AF: 0.00247 AC: 54 AN: 21896

American (AMR) AF: 0.0828 AC: 687 AN: 8296

Ashkenazi Jewish (ASJ) AF: 0.00178 AC: 4 AN: 2250

East Asian (EAS) AF: 0.0497 AC: 152 AN: 3056

South Asian (SAS) AF: 0.00314 AC: 8 AN: 2550

European-Finnish (FIN) AF: 0.00626 AC: 24 AN: 3836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 118

European-Non Finnish (NFE) AF: 0.00116 AC: 48 AN: 41534

Other (OTH) AF: 0.0195 AC: 23 AN: 1182

Alfa AF: 0.00 Hom.: 11

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73
Mutation Taster		=98/2	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;