7-66988489-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I212S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (78 hom., cov: 32)
  • Exomes 𝑓: 0.033 (985 hom.)
• Consequence: SBDS NM_016038.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 6.52

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]

ACMG classification

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 17 pathogenic changes around while only 2 benign (89%) 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 GnomAd at 78 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SBDS	NM_016038.4	c.635T>C	p.Ile212Thr	missense_variant	5/5	ENST00000246868.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SBDS	ENST00000246868.7	c.635T>C	p.Ile212Thr	missense_variant	5/5	1	NM_016038.4	P1

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3903 AN: 152168 Hom.: 78 Cov.: 32

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

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.: 31 AF XY: 0.0327 AC XY: 23761 AN XY: 727010

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.: 78 Cov.: 32 AF XY: 0.0247 AC XY: 1840 AN XY: 74482

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.: 66

Bravo AF: 0.0277

TwinsUK AF: 0.0359 AC: 133

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0388 AC: 334

ExAC AF: 0.0248 AC: 3006

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0430

EpiControl AF: 0.0419

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Shwachman-Diamond syndrome 1 Benign:5

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 21, 2015	- -
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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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. -

not provided Benign:1

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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0082	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
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	T
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

Other links and lift over

dbSNP: rs79344818; hg19: chr7-66453476; COSMIC: COSV55886995; COSMIC: COSV55886995;