7-66988471-C-T

Position:

• chr7-66988471-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SBDS NM_016038.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.01

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 Pathogenic. Variant got 14 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
• 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 [Likely_pathogenic]. Clinvar id is 1328553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SBDS	NM_016038.4	c.653G>A	p.Arg218Gln	missense_variant	5/5	ENST00000246868.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SBDS	ENST00000246868.7	c.653G>A	p.Arg218Gln	missense_variant	5/5	1	NM_016038.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251282 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135850

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: 5 AN: 1461596 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727112

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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
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	D
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

Other links and lift over

dbSNP: rs757497272; hg19: chr7-66453458;