chr8-93780659-G-A

Variant names:

• chr8-93780659-G-A
• rs35793208
• NM_153704.6:c.781G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153704.6(TMEM67):​c.781G>A​(p.Asp261Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,613,938 control chromosomes in the GnomAD database, including 219 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D261D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.014 (203 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.43
• Publications: 12 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 -18 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, 6 uncertain in NM_153704.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037896931).
• BP6: Variant 8-93780659-G-A is Benign according to our data. Variant chr8-93780659-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0119 (1814/152172) while in subpopulation SAS AF = 0.0264 (127/4818). AF 95% confidence interval is 0.0226. There are 16 homozygotes in GnomAd4. There are 951 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

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.781G>A	p.Asp261Asn	missense	Exon 8 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.538G>A	p.Asp180Asn	missense	Exon 9 of 29	NP_001135773.1	Q5HYA8
	TMEM67	NR_024522.2		n.802G>A		non_coding_transcript_exon	Exon 8 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.781G>A	p.Asp261Asn	missense	Exon 8 of 28	ENSP00000389998.3	Q5HYA8
	TMEM67	ENST00000452276.6	TSL:1	c.781G>A	p.Asp261Asn	missense	Exon 8 of 27	ENSP00000388671.2	C9JRQ8
	TMEM67	ENST00000474944.5	TSL:1	n.427-5564G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1814 AN: 152054 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0151 AC: 3784 AN: 251334 AF XY: 0.0163

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00809

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0341

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0137 AC: 19994 AN: 1461766 Hom.: 203 Cov.: 32 AF XY: 0.0143 AC XY: 10398 AN XY: 727186

African (AFR) AF: 0.00251 AC: 84 AN: 33480

American (AMR) AF: 0.00897 AC: 401 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 277 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0250 AC: 2159 AN: 86242

European-Finnish (FIN) AF: 0.0318 AC: 1695 AN: 53358

Middle Eastern (MID) AF: 0.0193 AC: 111 AN: 5766

European-Non Finnish (NFE) AF: 0.0130 AC: 14408 AN: 1111982

Other (OTH) AF: 0.0142 AC: 859 AN: 60396

GnomAD4 genome AF: 0.0119 AC: 1814 AN: 152172 Hom.: 16 Cov.: 32 AF XY: 0.0128 AC XY: 951 AN XY: 74398

African (AFR) AF: 0.00268 AC: 111 AN: 41486

American (AMR) AF: 0.0139 AC: 213 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0264 AC: 127 AN: 4818

European-Finnish (FIN) AF: 0.0297 AC: 314 AN: 10572

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0141 AC: 960 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0134 Hom.: 58

Bravo AF: 0.00984

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.0145 AC: 1761

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0147

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	1	Meckel syndrome, type 3 (1)
-	-	1	Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.26	N
PhyloP100		3.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.24
Sift	Benign	0.62	T
Sift4G	Benign	0.74	T
Polyphen		0.0050	B
Vest4		0.026
MPC		0.12
ClinPred		0.0022	T
GERP RS		2.8
Varity_R		0.037
gMVP		0.52
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: rs35793208; hg19: chr8-94792887; COSMIC: COSV60042655; COSMIC: COSV60042655;