chr17-58214784-G-A

Variant names:

• chr17-58214784-G-A
• rs386834050
• NM_017777.4:c.472C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_017777.4(MKS1):​c.472C>T​(p.Arg158*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005359515: Functional studies using HEK293 cells and fibroblasts from the compound heterozygous patient in the Khaddour et al. paper show that these variants result in ciliary defects, deregulation of proteasome, and disrupt Wnt/beta-catenin signaling (Szymanska et al. 2022. PubMed ID: 35170427).". Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MKS1 NM_017777.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.10
• Publications: 3 publications found

Genes affected

MKS1 (HGNC:7121): (MKS transition zone complex subunit 1) The protein encoded by this gene localizes to the basal body and is required for formation of the primary cilium in ciliated epithelial cells. Mutations in this gene result in Meckel syndrome type 1 and in Bardet-Biedl syndrome type 13. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

MKS1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Meckel syndrome, type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• Bardet-Biedl syndrome 13

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• Joubert syndrome 28

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005359515: Functional studies using HEK293 cells and fibroblasts from the compound heterozygous patient in the Khaddour et al. paper show that these variants result in ciliary defects, deregulation of proteasome, and disrupt Wnt/beta-catenin signaling (Szymanska et al. 2022. PubMed ID: 35170427).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-58214784-G-A is Pathogenic according to our data. Variant chr17-58214784-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 56623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017777.4. 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
	MKS1	NM_017777.4	MANE Select	c.472C>T	p.Arg158*	stop_gained	Exon 5 of 18	NP_060247.2	Q9NXB0-1
	MKS1	NM_001321269.2		c.472C>T	p.Arg158*	stop_gained	Exon 5 of 17	NP_001308198.1	A0A7I2V2M0
	MKS1	NM_001330397.2		c.472C>T	p.Arg158*	stop_gained	Exon 5 of 16	NP_001317326.1	H0Y2S2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	ENST00000393119.7	TSL:1 MANE Select	c.472C>T	p.Arg158*	stop_gained	Exon 5 of 18	ENSP00000376827.2	Q9NXB0-1
	MKS1	ENST00000537529.7	TSL:1	c.43C>T	p.Arg15*	stop_gained	Exon 5 of 18	ENSP00000442096.3	A0A0S2Z5Z2
	MKS1	ENST00000966002.1		c.472C>T	p.Arg158*	stop_gained	Exon 5 of 18	ENSP00000636061.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 244582 AF XY: 0.00000751

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454812 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723996

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000447 AC: 2 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111776

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Bardet-Biedl syndrome 13 (1)
1	-	-	Meckel syndrome, type 1 (1)
1	-	-	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
1	-	-	MKS1-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		2.1
Vest4		0.93
GERP RS		5.7
PromoterAI		-0.019	Neutral
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs386834050; hg19: chr17-56292145;