7-66988489-A-G

Position:

chr7-66988489-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_016038.4(SBDS):c.635T>C(p.Ile212Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0326 in 1,613,618 control chromosomes in the GnomAD database, including 1,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 78 hom., cov: 32)

Exomes 𝑓: 0.033 ( 985 hom. )

Consequence

SBDS
NM_016038.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 6.52

Variant links:

Genes affected

SBDS (HGNC:19440): (SBDS ribosome maturation factor) This gene encodes a highly conserved protein that plays an essential role in ribosome biogenesis. The encoded protein interacts with elongation factor-like GTPase 1 to disassociate eukaryotic initiation factor 6 from the late cytoplasmic pre-60S ribosomal subunit allowing assembly of the 80S subunit. Mutations within this gene are associated with the autosomal recessive disorder Shwachman-Bodian-Diamond syndrome. This gene has a closely linked pseudogene that is distally located. [provided by RefSeq, Jan 2017]

SBDS links:

SBDS (HGNC:):

SBDS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Ribosome maturation protein SBDS (size 248) in uniprot entity SBDS_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_016038.4

BP4

Computational evidence support a benign effect (MetaRNN=0.008209795).

BP6

Variant 7-66988489-A-G is Benign according to our data. Variant chr7-66988489-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 21543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66988489-A-G is described in Lovd as [Benign]. Variant chr7-66988489-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0256 (3903/152286) while in subpopulation AMR AF= 0.0399 (610/15282). AF 95% confidence interval is 0.0373. There are 78 homozygotes in gnomad4. There are 1840 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 78 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SBDS	NM_016038.4 linkuse as main transcript	c.635T>C	p.Ile212Thr	missense_variant	5/5	ENST00000246868.7	NP_057122.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SBDS	ENST00000246868.7 linkuse as main transcript	c.635T>C	p.Ile212Thr	missense_variant	5/5	1	NM_016038.4	ENSP00000246868.2		Q9Y3A5

Frequencies

GnomAD3 genomes

AF:

0.0256

AC:

3903

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00883

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.0400

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.00809

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0366

Gnomad OTH

AF:

0.0430

GnomAD3 exomes

AF:

0.0253

AC:

6356

AN:

251168

Hom.:

124

AF XY:

0.0253

AC XY:

3432

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00664

Gnomad AMR exome

AF:

0.0293

Gnomad ASJ exome

AF:

0.0392

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0110

Gnomad FIN exome

AF:

0.00943

Gnomad NFE exome

AF:

0.0363

Gnomad OTH exome

AF:

0.0285

GnomAD4 exome

AF:

0.0333

AC:

48623

AN:

1461332

Hom.:

985

Cov.:

AF XY:

0.0327

AC XY:

23761

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.00597

Gnomad4 AMR exome

AF:

0.0296

Gnomad4 ASJ exome

AF:

0.0372

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0119

Gnomad4 FIN exome

AF:

0.00933

Gnomad4 NFE exome

AF:

0.0382

Gnomad4 OTH exome

AF:

0.0319

GnomAD4 genome

AF:

0.0256

AC:

3903

AN:

152286

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

1840

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00881

Gnomad4 AMR

AF:

0.0399

Gnomad4 ASJ

AF:

0.0351

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0124

Gnomad4 FIN

AF:

0.00809

Gnomad4 NFE

AF:

0.0366

Gnomad4 OTH

AF:

0.0426

Alfa

AF:

0.0330

Hom.:

Bravo

AF:

0.0277

TwinsUK

AF:

0.0359

AC:

133

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0388

AC:

334

ExAC

AF:

0.0248

AC:

3006

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0430

EpiControl

AF:

0.0419

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 05, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 363/13006=2.79% -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Shwachman-Diamond syndrome 1

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Shwachman-Diamond syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27153395, 27884173, 12496757, 21228398, 15701631, 22995991) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0082

T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.5

D;.

REVEL

Uncertain

0.62

Sift

Uncertain

0.028

D;.

Sift4G

Uncertain

0.017

D;D

Polyphen

0.15

B;.

Vest4

0.55

MPC

0.73

ClinPred

0.063

GERP RS

2.6

Varity_R

0.39

gMVP

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over