rs201619500

chr17-58207104-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5 BP4_Strong BS2

The NM_017777.4(MKS1):c.1388G>A(p.Arg463Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00261 in 1,614,132 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R463G) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0023 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: MKS1 NM_017777.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:12
• Conservation: PhyloP100: 5.70

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-58207105-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 582164.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008825868).
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKS1	NM_017777.4	c.1388G>A	p.Arg463Gln	missense_variant	15/18	ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7	c.1388G>A	p.Arg463Gln	missense_variant	15/18	1	NM_017777.4	P1

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152134 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00220 AC: 548 AN: 249540 Hom.: 3 AF XY: 0.00222 AC XY: 301 AN XY: 135396

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.000696

Gnomad NFE exome AF: 0.00288

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00264 AC: 3863 AN: 1461880 Hom.: 11 Cov.: 31 AF XY: 0.00260 AC XY: 1893 AN XY: 727238

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00277

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00229 AC: 348 AN: 152252 Hom.: 7 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74448

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00248

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00335 Hom.: 4

Bravo AF: 0.00264

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00302 AC: 25

ExAC AF: 0.00212 AC: 256

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MKS1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2020	This variant is associated with the following publications: (PMID: 27353947, 31456290) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 09, 2017	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 14, 2023	Variant summary: MKS1 c.1388G>A (p.Arg463Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 249540 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.96 fold of the estimated maximal expected allele frequency for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1388G>A in individuals affected with Meckel Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (likely pathogenic n=1, VUS n=1, likely benign/benign n=7). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2016	- -

Meckel syndrome, type 1 Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Bardet-Biedl syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Bardet-Biedl syndrome 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	0.091
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.19
Sift	Benign	0.15	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.17	B;.
Vest4		0.65
MVP		0.64
MPC		0.34
ClinPred		0.035	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs201619500; hg19: chr17-56284465; COSMIC: COSV99836882; COSMIC: COSV99836882;