rs34304018

Variant names:

• chr17-58206040-AT-A
• rs34304018
• NM_017777.4:c.*38delA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_017777.4(MKS1):​c.*38delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,582,762 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: MKS1 NM_017777.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.27
• Publications: 0 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):

• Meckel syndrome, type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-58206040-AT-A is Benign according to our data. Variant chr17-58206040-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1187069.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 = 0.00293 (446/152222) while in subpopulation AFR AF = 0.0105 (437/41546). AF 95% confidence interval is 0.0097. There are 4 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4	c.*38delA		3_prime_UTR_variant	Exon 18 of 18	ENST00000393119.7	NP_060247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7	c.*38delA		3_prime_UTR_variant	Exon 18 of 18	1	NM_017777.4	ENSP00000376827.2

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152106 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.000478

GnomAD2 exomes AF: 0.000638 AC: 127 AN: 199158 AF XY: 0.000408

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000381

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000230

Gnomad OTH exome AF: 0.000196

GnomAD4 exome AF: 0.000277 AC: 396 AN: 1430540 Hom.: 3 Cov.: 32 AF XY: 0.000221 AC XY: 157 AN XY: 709208

African (AFR) AF: 0.0109 AC: 355 AN: 32690

American (AMR) AF: 0.000404 AC: 16 AN: 39570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25550

East Asian (EAS) AF: 0.00 AC: 0 AN: 38166

South Asian (SAS) AF: 0.00 AC: 0 AN: 82826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4454

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1097486

Other (OTH) AF: 0.000372 AC: 22 AN: 59190

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152222 Hom.: 4 Cov.: 32 AF XY: 0.00278 AC XY: 207 AN XY: 74444

African (AFR) AF: 0.0105 AC: 437 AN: 41546

American (AMR) AF: 0.000523 AC: 8 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00143 Hom.: 1

Bravo AF: 0.00318

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MKS1: BS1, BS2 -

Aug 12, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
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: rs34304018; hg19: chr17-56283401;