rs79833026

Variant names:

• chr8-93754889-G-C
• rs79833026
• NM_001142301.1:c.-200G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-93754889-G-C
• chr8-93754889-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001142301.1(TMEM67):​c.-200G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,607,400 control chromosomes in the GnomAD database, including 153 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 (87 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (66 hom.)
• Consequence: TMEM67 NM_001142301.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.200
• 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, 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=-0.83).
• BP6: Variant 8-93754889-G-C is Benign according to our data. Variant chr8-93754889-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0593 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142301.1. 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_001142301.1		c.-200G>C		5_prime_UTR	Exon 1 of 29	NP_001135773.1	Q5HYA8
	TMEM67	NM_153704.6	MANE Select	c.-26G>C		upstream_gene	N/A	NP_714915.3
	TMEM67	NR_024522.2		n.-5G>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000684064.1		c.-225G>C		5_prime_UTR	Exon 1 of 29	ENSP00000508192.1	A0A804HL43
	TMEM67	ENST00000518319.5	TSL:4	c.-431G>C		5_prime_UTR	Exon 1 of 8	ENSP00000430289.1	E5RG10
	TMEM67	ENST00000498673.5	TSL:4	c.-438G>C		5_prime_UTR	Exon 1 of 5	ENSP00000430232.1

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2769 AN: 152176 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.00469 AC: 1174 AN: 250244 AF XY: 0.00366

Gnomad AFR exome AF: 0.0628

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00180 AC: 2613 AN: 1455106 Hom.: 66 Cov.: 30 AF XY: 0.00155 AC XY: 1120 AN XY: 724316

African (AFR) AF: 0.0614 AC: 2044 AN: 33290

American (AMR) AF: 0.00447 AC: 200 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000805 AC: 21 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00232 AC: 11 AN: 4738

European-Non Finnish (NFE) AF: 0.0000533 AC: 59 AN: 1107150

Other (OTH) AF: 0.00437 AC: 263 AN: 60132

GnomAD4 genome AF: 0.0183 AC: 2785 AN: 152294 Hom.: 87 Cov.: 32 AF XY: 0.0178 AC XY: 1325 AN XY: 74470

African (AFR) AF: 0.0613 AC: 2548 AN: 41552

American (AMR) AF: 0.0120 AC: 183 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.00988 Hom.: 11

Bravo AF: 0.0210

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Joubert syndrome 6 (1)
-	-	1	Meckel syndrome, type 3 (1)
-	-	1	Nephronophthisis 11 (1)
-	-	1	TMEM67-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.23
DANN	Benign	0.37
PhyloP100		-0.20
PromoterAI		0.019	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs79833026; hg19: chr8-94767117;