NM_153704.6:c.1774-45A>C

Variant names:

• chr8-93795856-A-C
• rs73694960
• NM_153704.6:c.1774-45A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153704.6(TMEM67):​c.1774-45A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,416,354 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: TMEM67 NM_153704.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.197
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 8-93795856-A-C is Benign according to our data. Variant chr8-93795856-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 126300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00723 (1101/152260) while in subpopulation AFR AF = 0.0216 (899/41556). AF 95% confidence interval is 0.0205. There are 15 homozygotes in GnomAd4. There are 518 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	NM_153704.6	MANE Select	c.1774-45A>C		intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.1531-45A>C		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.1795-45A>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.1774-45A>C		intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.1774-45A>C		intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.912-45A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00720 AC: 1096 AN: 152142 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00930

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00241 AC: 550 AN: 228654 AF XY: 0.00197

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000828

Gnomad FIN exome AF: 0.0000954

Gnomad NFE exome AF: 0.000549

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.00106 AC: 1336 AN: 1264094 Hom.: 4 Cov.: 17 AF XY: 0.000969 AC XY: 618 AN XY: 637610

African (AFR) AF: 0.0224 AC: 625 AN: 27904

American (AMR) AF: 0.00322 AC: 121 AN: 37620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24046

East Asian (EAS) AF: 0.000310 AC: 12 AN: 38702

South Asian (SAS) AF: 0.000741 AC: 57 AN: 76930

European-Finnish (FIN) AF: 0.0000569 AC: 3 AN: 52678

Middle Eastern (MID) AF: 0.00151 AC: 8 AN: 5300

European-Non Finnish (NFE) AF: 0.000406 AC: 385 AN: 947546

Other (OTH) AF: 0.00234 AC: 125 AN: 53368

GnomAD4 genome AF: 0.00723 AC: 1101 AN: 152260 Hom.: 15 Cov.: 32 AF XY: 0.00696 AC XY: 518 AN XY: 74450

African (AFR) AF: 0.0216 AC: 899 AN: 41556

American (AMR) AF: 0.00935 AC: 143 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68004

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00449 Hom.: 1

Bravo AF: 0.00864

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.51
DANN	Benign	0.15
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism

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: rs73694960; hg19: chr8-94808084; COSMIC: COSV60038688; COSMIC: COSV60038688;