7-66988421-C-G

Variant names:

• chr7-66988421-C-G
• NM_016038.4:c.703G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_016038.4(SBDS):​c.703G>C​(p.Glu235Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SBDS NM_016038.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SBDS	NM_016038.4	c.703G>C	p.Glu235Gln	missense_variant	Exon 5 of 5	ENST00000246868.7	NP_057122.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SBDS	ENST00000246868.7	c.703G>C	p.Glu235Gln	missense_variant	Exon 5 of 5	1	NM_016038.4	ENSP00000246868.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461586 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727116

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E235Q variant (also known as c.703G>C), located in coding exon 5 of the SBDS gene, results from a G to C substitution at nucleotide position 703. The glutamic acid at codon 235 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.67
Sift	Benign	0.058	T;.
Sift4G	Uncertain	0.057	T;T
Polyphen		0.62	P;.
Vest4		0.40
MutPred		0.34		Loss of ubiquitination at K231 (P = 0.0573);Loss of ubiquitination at K231 (P = 0.0573);
MVP		0.98
MPC		1.2
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.70
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-66453408;