NM_153704.6:c.224G>T

Variant names:

• chr8-93755778-G-T
• rs780823805
• NM_153704.6:c.224G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_153704.6(TMEM67):​c.224G>T​(p.Gly75Val) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G75E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM67 NM_153704.6 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.51
• 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 3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_153704.6
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.224G>T	p.Gly75Val	missense splice_region	Exon 2 of 28	NP_714915.3
	TMEM67	NR_024522.2		n.245G>T		splice_region non_coding_transcript_exon	Exon 2 of 29
	TMEM67	NM_001142301.1		c.-62+641G>T		intron	N/A	NP_001135773.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.224G>T	p.Gly75Val	missense splice_region	Exon 2 of 28	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224G>T	p.Gly75Val	missense splice_region	Exon 2 of 27	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244G>T		splice_region non_coding_transcript_exon	Exon 2 of 17

Frequencies

GnomAD3 genomes AF: 0.0000162 AC: 2 AN: 123304 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000132 AC: 90 AN: 680764 Hom.: 0 Cov.: 14 AF XY: 0.000115 AC XY: 41 AN XY: 355970

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000133 AC: 2 AN: 15014

American (AMR) AF: 0.00 AC: 0 AN: 26134

Ashkenazi Jewish (ASJ) AF: 0.0000605 AC: 1 AN: 16530

East Asian (EAS) AF: 0.00 AC: 0 AN: 28414

South Asian (SAS) AF: 0.0000589 AC: 3 AN: 50898

European-Finnish (FIN) AF: 0.0000226 AC: 1 AN: 44180

Middle Eastern (MID) AF: 0.000415 AC: 1 AN: 2410

European-Non Finnish (NFE) AF: 0.000171 AC: 80 AN: 466684

Other (OTH) AF: 0.0000656 AC: 2 AN: 30500

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000162 AC: 2 AN: 123304 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 58232

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000649 AC: 2 AN: 30802

American (AMR) AF: 0.00 AC: 0 AN: 11210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3256

East Asian (EAS) AF: 0.00 AC: 0 AN: 4346

South Asian (SAS) AF: 0.00 AC: 0 AN: 4088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61402

Other (OTH) AF: 0.00 AC: 0 AN: 1646

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.5
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.70
Sift	Benign	0.034	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.79
MutPred		0.49		Loss of disorder (P = 0.0653)
MVP		1.0
MPC		0.62
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.48
gMVP		0.89
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs780823805; hg19: chr8-94768006;