17-58207855-G-A

Variant names:

• chr17-58207855-G-A
• rs117007334
• NM_017777.4:c.1273+39C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_017777.4(MKS1):​c.1273+39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,540,370 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (9 hom.)
• Consequence: MKS1 NM_017777.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.298
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-58207855-G-A is Benign according to our data. Variant chr17-58207855-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 260881.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	NM_017777.4	MANE Select	c.1273+39C>T		intron	N/A	NP_060247.2
	MKS1	NM_001321269.2		c.1273+39C>T		intron	N/A	NP_001308198.1
	MKS1	NM_001330397.2		c.1273+39C>T		intron	N/A	NP_001317326.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	ENST00000393119.7	TSL:1 MANE Select	c.1273+39C>T		intron	N/A	ENSP00000376827.2
	MKS1	ENST00000537529.7	TSL:1	c.844+39C>T		intron	N/A	ENSP00000442096.3
	MKS1	ENST00000585134.2	TSL:2	c.1312C>T	p.Leu438Leu	synonymous	Exon 14 of 14	ENSP00000463826.2

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00143 AC: 355 AN: 247722 AF XY: 0.00143

Gnomad AFR exome AF: 0.000325

Gnomad AMR exome AF: 0.000988

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00117 AC: 1630 AN: 1388066 Hom.: 9 Cov.: 26 AF XY: 0.00123 AC XY: 851 AN XY: 694518

African (AFR) AF: 0.000282 AC: 9 AN: 31880

American (AMR) AF: 0.000943 AC: 42 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 325 AN: 25700

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39306

South Asian (SAS) AF: 0.000378 AC: 32 AN: 84648

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53304

Middle Eastern (MID) AF: 0.00657 AC: 35 AN: 5328

European-Non Finnish (NFE) AF: 0.00102 AC: 1068 AN: 1045416

Other (OTH) AF: 0.00193 AC: 112 AN: 57932

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74468

African (AFR) AF: 0.000144 AC: 6 AN: 41568

American (AMR) AF: 0.000654 AC: 10 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00305 Hom.: 2

Bravo AF: 0.00114

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00190

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

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	-0.82
CADD	Benign	9.2
DANN	Benign	0.63
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs117007334; hg19: chr17-56285216;