rs797046043

Variant names:

• chr8-93755825-G-A
• rs797046043
• NM_153704.6:c.271G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_153704.6(TMEM67):​c.271G>A​(p.Gly91Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,371,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G91G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_153704.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.271G>A	p.Gly91Arg	missense_variant	Exon 2 of 28	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.271G>A	p.Gly91Arg	missense_variant	Exon 2 of 28	1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1371208 Hom.: 0 Cov.: 29 AF XY: 0.00000147 AC XY: 1 AN XY: 682536

African (AFR) AF: 0.00 AC: 0 AN: 31164

American (AMR) AF: 0.00 AC: 0 AN: 42426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23408

East Asian (EAS) AF: 0.00 AC: 0 AN: 35068

South Asian (SAS) AF: 0.00 AC: 0 AN: 81188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5316

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1048786

Other (OTH) AF: 0.0000182 AC: 1 AN: 55060

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 15, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	2.9	M;.
PhyloP100		3.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.039	D;D
Sift4G	Benign	0.098	T;D
Polyphen		0.98	D;.
Vest4		0.52
MutPred		0.55		Loss of stability (P = 0.2774);Loss of stability (P = 0.2774);
MVP		0.99
MPC		0.39
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.25
gMVP		0.72
Mutation Taster		=64/36	polymorphism

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: rs797046043; hg19: chr8-94768053;