rs117195541

Variant names:

• chr8-93804836-T-C
• rs117195541
• NM_153704.6:c.2397T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_153704.6(TMEM67):​c.2397T>C​(p.Asp799Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,604,908 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 30)
  • Exomes 𝑓: 0.017 (256 hom.)
• Consequence: TMEM67 NM_153704.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13
• Conservation: PhyloP100: 0.853
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 8-93804836-T-C is Benign according to our data. Variant chr8-93804836-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.853 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0126 (1924/152206) while in subpopulation SAS AF = 0.0199 (96/4822). AF 95% confidence interval is 0.0178. There are 19 homozygotes in GnomAd4. There are 945 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.2397T>C	p.Asp799Asp	synonymous	Exon 23 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.2154T>C	p.Asp718Asp	synonymous	Exon 24 of 29	NP_001135773.1
	TMEM67	NR_024522.2		n.2418T>C		non_coding_transcript_exon	Exon 23 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.2397T>C	p.Asp799Asp	synonymous	Exon 23 of 28	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.2322+1152T>C		intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.1535T>C		non_coding_transcript_exon	Exon 14 of 17

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1924 AN: 152088 Hom.: 19 Cov.: 30

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0153 AC: 3851 AN: 251028 AF XY: 0.0165

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00843

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0169 AC: 24509 AN: 1452702 Hom.: 256 Cov.: 27 AF XY: 0.0171 AC XY: 12367 AN XY: 723304

African (AFR) AF: 0.00198 AC: 66 AN: 33294

American (AMR) AF: 0.00824 AC: 368 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00948 AC: 247 AN: 26060

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39552

South Asian (SAS) AF: 0.0226 AC: 1946 AN: 86046

European-Finnish (FIN) AF: 0.0142 AC: 756 AN: 53356

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5744

European-Non Finnish (NFE) AF: 0.0182 AC: 20077 AN: 1103880

Other (OTH) AF: 0.0160 AC: 959 AN: 60094

GnomAD4 genome AF: 0.0126 AC: 1924 AN: 152206 Hom.: 19 Cov.: 30 AF XY: 0.0127 AC XY: 945 AN XY: 74414

African (AFR) AF: 0.00291 AC: 121 AN: 41534

American (AMR) AF: 0.0127 AC: 194 AN: 15286

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

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4822

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10576

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0187 AC: 1269 AN: 68018

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.0172 Hom.: 48

Bravo AF: 0.0116

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0201

EpiControl AF: 0.0198

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	1	-	Bardet-Biedl syndrome 14 (1)
-	-	1	Joubert syndrome 6 (1)
-	-	1	Kidney disorder (1)
-	-	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;C0431399:Joubert syndrome (1)
-	-	1	Nephronophthisis 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.1
DANN	Benign	0.60
PhyloP100		0.85
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: rs117195541; hg19: chr8-94817064;