rs190249177

Variant names:

• chr8-93755815-C-T
• rs190249177
• NM_153704.6:c.261C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_153704.6(TMEM67):​c.261C>T​(p.Ile87Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,234,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: TMEM67 NM_153704.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.363
• 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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.136).
• BP6: Variant 8-93755815-C-T is Benign according to our data. Variant chr8-93755815-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 262746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.363 with no splicing effect.

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.261C>T	p.Ile87Ile	synonymous	Exon 2 of 28	NP_714915.3
	TMEM67	NR_024522.2		n.282C>T		non_coding_transcript_exon	Exon 2 of 29
	TMEM67	NM_001142301.1		c.-62+678C>T		intron	N/A	NP_001135773.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.261C>T	p.Ile87Ile	synonymous	Exon 2 of 28	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.261C>T	p.Ile87Ile	synonymous	Exon 2 of 27	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.281C>T		non_coding_transcript_exon	Exon 2 of 17

Frequencies

GnomAD3 genomes AF: 0.0000422 AC: 5 AN: 118524 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000812

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000413 AC: 1 AN: 242408 AF XY: 0.00000763

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000367 AC: 41 AN: 1116168 Hom.: 0 Cov.: 27 AF XY: 0.0000374 AC XY: 21 AN XY: 561522

African (AFR) AF: 0.0000392 AC: 1 AN: 25514

American (AMR) AF: 0.00 AC: 0 AN: 39252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19946

East Asian (EAS) AF: 0.00 AC: 0 AN: 28330

South Asian (SAS) AF: 0.00 AC: 0 AN: 75568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4280

European-Non Finnish (NFE) AF: 0.0000479 AC: 40 AN: 835650

Other (OTH) AF: 0.00 AC: 0 AN: 44592

GnomAD4 genome AF: 0.0000422 AC: 5 AN: 118566 Hom.: 0 Cov.: 29 AF XY: 0.0000365 AC XY: 2 AN XY: 54840

African (AFR) AF: 0.00 AC: 0 AN: 30160

American (AMR) AF: 0.00 AC: 0 AN: 9216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3294

East Asian (EAS) AF: 0.00 AC: 0 AN: 3712

South Asian (SAS) AF: 0.00 AC: 0 AN: 3588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 124

European-Non Finnish (NFE) AF: 0.0000812 AC: 5 AN: 61564

Other (OTH) AF: 0.00 AC: 0 AN: 1552

Alfa AF: 0.0000403 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.1
DANN	Benign	0.69
PhyloP100		-0.36

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: rs190249177; hg19: chr8-94768043;