7-66988471-C-T

Position:

chr7-66988471-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_016038.4(SBDS):c.653G>A(p.Arg218Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SBDS
NM_016038.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.01

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 Likely_pathogenic. Variant got 7 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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 7-66988471-C-T is Pathogenic according to our data. Variant chr7-66988471-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1328553.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SBDS	NM_016038.4 linkuse as main transcript	c.653G>A	p.Arg218Gln	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.653G>A	p.Arg218Gln	missense_variant	5/5	1	NM_016038.4	ENSP00000246868.2		Q9Y3A5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251282

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461596

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aplastic anemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 01, 2023

- -

Shwachman-Diamond syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 13, 2021

The SBDS c.653G>A (p.Arg218Gln) variant is a missense variant that is reported in three unrelated individuals with Shwachman-Diamond syndrome. Donadieu et al. (2012) identified one patient who carried the p.Arg218Gln variant in a presumed compound heterozygous state with a p.Cys84fs variant, which was noted to result from either c.258+2T>C or c.258+1G>A, while Ipatova et al. (2019) found two unrelated patients who carried the p.Arg218Gln variant in a presumed compound heterozygous state with a c.258+2T>C variant. The p.Arg218Gln variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1), though this is based on only a single allele in a region of good sequencing coverage, suggesting that the variant is rare. Weis at el. (2015) suggest that the highly conserved Arg218 residue may make electrostatic interactions with the tip of a helix portion of the protein to help provide stability during binding to EFL1. Multiple computational analyses suggest that the p.Arg218Gln variant would negatively impact the protein, though these predictions have not been experimentally confirmed. Based on the available evidence, the p.Arg218Gln variant is classified as likely pathogenic for Shwachman-Diamond syndrome. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 25, 2024

Variant summary: SBDS c.653G>A (p.Arg218Gln) results in a conservative amino acid change located in the Ribosome maturation protein SDO1/SBDS, C-terminal domain (IPR046928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.653G>A in individuals affected with Shwachman-Diamond Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1328553). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;T

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.5

D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;.

Vest4

0.55

MutPred

0.86

Gain of disorder (P = 0.1446);Gain of disorder (P = 0.1446);

MVP

0.97

MPC

1.4

ClinPred

1.0

GERP RS

5.0

Varity_R

0.96

gMVP

0.64

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