rs56307046

Variant names:

• chr8-93816329-C-T
• rs56307046
• NM_153704.6:c.2908-43C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-93816329-C-T
• chr8-93816329-C-A

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.2908-43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 970,454 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (85 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (45 hom.)
• Consequence: TMEM67 NM_153704.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.918
• 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, STRONG Submitted by: PanelApp Australia, 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: Ambry Genetics, Orphanet
• 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=-0.93).
• BP6: Variant 8-93816329-C-T is Benign according to our data. Variant chr8-93816329-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0596 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	NM_153704.6	MANE Select	c.2908-43C>T		intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.2665-43C>T		intron	N/A	NP_001135773.1	Q5HYA8
	TMEM67	NR_024522.2		n.2929-43C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.2908-43C>T		intron	N/A	ENSP00000389998.3	Q5HYA8
	TMEM67	ENST00000452276.6	TSL:1	c.2791-43C>T		intron	N/A	ENSP00000388671.2	C9JRQ8
	TMEM67	ENST00000520680.2	TSL:3	c.3031-43C>T		intron	N/A	ENSP00000428785.2	H0YB69

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2776 AN: 152028 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.0613

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00463 AC: 1012 AN: 218534 AF XY: 0.00373

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.000590

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00234

GnomAD4 exome AF: 0.00200 AC: 1639 AN: 818308 Hom.: 45 Cov.: 11 AF XY: 0.00169 AC XY: 724 AN XY: 427154

African (AFR) AF: 0.0620 AC: 1237 AN: 19948

American (AMR) AF: 0.00462 AC: 157 AN: 34012

Ashkenazi Jewish (ASJ) AF: 0.000644 AC: 13 AN: 20200

East Asian (EAS) AF: 0.00 AC: 0 AN: 35762

South Asian (SAS) AF: 0.000218 AC: 13 AN: 59708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50430

Middle Eastern (MID) AF: 0.00185 AC: 7 AN: 3786

European-Non Finnish (NFE) AF: 0.0000665 AC: 37 AN: 556386

Other (OTH) AF: 0.00460 AC: 175 AN: 38076

GnomAD4 genome AF: 0.0184 AC: 2792 AN: 152146 Hom.: 85 Cov.: 33 AF XY: 0.0178 AC XY: 1325 AN XY: 74398

African (AFR) AF: 0.0615 AC: 2554 AN: 41500

American (AMR) AF: 0.0120 AC: 184 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67982

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.00966 Hom.: 17

Bravo AF: 0.0210

Asia WGS AF: 0.00376 AC: 13 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.74
DANN	Benign	0.47
PhyloP100		-0.92
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: rs56307046; hg19: chr8-94828557;