NM_153704.6:c.1810A>G

Variant names:

• chr8-93795937-A-G
• rs3134031
• NM_153704.6:c.1810A>G

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.1810A>G​(p.Ile604Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,610,204 control chromosomes in the GnomAD database, including 305,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32347 hom., cov: 33)
  • Exomes 𝑓: 0.61 (273246 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.282
• Publications: 46 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.642796E-7).
• BP6: Variant 8-93795937-A-G is Benign according to our data. Variant chr8-93795937-A-G is described in ClinVar as Benign. ClinVar VariationId is 126301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 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.1810A>G	p.Ile604Val	missense	Exon 18 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.1567A>G	p.Ile523Val	missense	Exon 19 of 29	NP_001135773.1
	TMEM67	NR_024522.2		n.1831A>G		non_coding_transcript_exon	Exon 18 of 29

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.1810A>G	p.Ile604Val	missense	Exon 18 of 28	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.1810A>G	p.Ile604Val	missense	Exon 18 of 27	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.948A>G		non_coding_transcript_exon	Exon 9 of 17

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98564 AN: 152010 Hom.: 32297 Cov.: 33

Gnomad AFR AF: 0.727

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.630

GnomAD2 exomes AF: 0.640 AC: 160774 AN: 251218 AF XY: 0.634

Gnomad AFR exome AF: 0.734

Gnomad AMR exome AF: 0.740

Gnomad ASJ exome AF: 0.660

Gnomad EAS exome AF: 0.734

Gnomad FIN exome AF: 0.573

Gnomad NFE exome AF: 0.597

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.610 AC: 889740 AN: 1458076 Hom.: 273246 Cov.: 36 AF XY: 0.610 AC XY: 442352 AN XY: 725528

African (AFR) AF: 0.738 AC: 24673 AN: 33414

American (AMR) AF: 0.730 AC: 32641 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 17312 AN: 26096

East Asian (EAS) AF: 0.722 AC: 28623 AN: 39668

South Asian (SAS) AF: 0.625 AC: 53806 AN: 86082

European-Finnish (FIN) AF: 0.579 AC: 30894 AN: 53392

Middle Eastern (MID) AF: 0.619 AC: 3563 AN: 5758

European-Non Finnish (NFE) AF: 0.596 AC: 660975 AN: 1108710

Other (OTH) AF: 0.618 AC: 37253 AN: 60250

GnomAD4 genome AF: 0.649 AC: 98676 AN: 152128 Hom.: 32347 Cov.: 33 AF XY: 0.649 AC XY: 48260 AN XY: 74354

African (AFR) AF: 0.727 AC: 30186 AN: 41520

American (AMR) AF: 0.680 AC: 10403 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 2290 AN: 3472

East Asian (EAS) AF: 0.730 AC: 3778 AN: 5174

South Asian (SAS) AF: 0.643 AC: 3104 AN: 4824

European-Finnish (FIN) AF: 0.572 AC: 6041 AN: 10564

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.599 AC: 40731 AN: 67970

Other (OTH) AF: 0.635 AC: 1343 AN: 2114

Alfa AF: 0.617 Hom.: 94721

Bravo AF: 0.660

TwinsUK AF: 0.601 AC: 2229

ALSPAC AF: 0.608 AC: 2344

ESP6500AA AF: 0.729 AC: 3211

ESP6500EA AF: 0.595 AC: 5117

ExAC AF: 0.637 AC: 77325

Asia WGS AF: 0.670 AC: 2334 AN: 3476

EpiCase AF: 0.599

EpiControl AF: 0.608

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Joubert syndrome 6 (2)
-	-	2	Meckel syndrome, type 3 (2)
-	-	2	Nephronophthisis 11 (2)
-	-	2	not provided (2)
-	-	1	COACH syndrome 1 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.9
DANN	Benign	0.71
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.058	T
MetaRNN	Benign	8.6e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.5	N
PhyloP100		0.28
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.17
Sift	Benign	0.48	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.097
ClinPred		0.00053	T
GERP RS		0.32
Varity_R		0.026
gMVP		0.19
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: rs3134031; hg19: chr8-94808165; COSMIC: COSV60038748; COSMIC: COSV60038748;