7-66995291-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_016038.4(SBDS):c.127G>T(p.Val43Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,556 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: SBDS NM_016038.4 missense, splice_region
• Scores: Splicing: ADA: 0.7986
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.73

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]

TYW1 (HGNC:25598): (tRNA-yW synthesizing protein 1 homolog) Wybutosine (yW) is a hypermodified guanosine found in phenylalanine tRNA adjacent to the anticodon that stabilizes codon-anticodon interactions in the ribosome. In yeast, the homolog of this gene is essential for the synthesis of wybutosine. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_benign. Variant got -3 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=0.04228115).
• BP6: Variant 7-66995291-C-A is Benign according to our data. Variant chr7-66995291-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378498.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr7-66995291-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SBDS	NM_016038.4	c.127G>T	p.Val43Leu	missense_variant, splice_region_variant	1/5	ENST00000246868.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SBDS	ENST00000246868.7	c.127G>T	p.Val43Leu	missense_variant, splice_region_variant	1/5	1	NM_016038.4	P1

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00117 AC: 293 AN: 251058 Hom.: 1 AF XY: 0.00113 AC XY: 153 AN XY: 135814

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00146 AC: 2138 AN: 1461188 Hom.: 2 Cov.: 31 AF XY: 0.00147 AC XY: 1068 AN XY: 726906

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000655

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000991 AC: 151 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000913 AC XY: 68 AN XY: 74516

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000839

ExAC AF: 0.00151 AC: 183

EpiCase AF: 0.00158

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2023	Observed in the heterozygous state with no second SBDS variant in patients with refractory cytopenia or suspected Shwachman-Diamond syndrome (Karow A et al., 2010; Thomassen JC et al., 2016; Rother C et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26136524, 31839986, 34151701, 19951977, 36835434) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SBDS p.Val43Leu variant was identified in 1 of 240 proband chromosomes (frequency: 0.0042) from individuals with primary hypocellular refractory cytopenia (Karow_2010_PMID:19951977). The variant was also reported as a heterozygous variant in a girl with cystic fibrosis and Shwachman-Bodian-Diamond Syndrome as a variant of unknown clinical significance (Thomassen_2016). The variant was identified in dbSNP (ID: rs147652512) LOVD 3.0 and ClinVar (classified as likely benign by GeneDx). The variant was identified in control databases in 302 of 268098 chromosomes (1 homozygous) at a frequency of 0.001126 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 254 of 118020 chromosomes (freq: 0.002152), Other in 8 of 6704 chromosomes (freq: 0.001193), European (Finnish) in 16 of 25094 chromosomes (freq: 0.000638), Latino in 15 of 35098 chromosomes (freq: 0.000427), African in 4 of 23554 chromosomes (freq: 0.00017), East Asian in 3 of 19246 chromosomes (freq: 0.000156) and South Asian in 2 of 30526 chromosomes (freq: 0.000066), but was not observed in the Ashkenazi Jewish population. The p.Val43 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Val43Leu variant occurs in the second last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing. Further, transcriptional studies did not reveal an effect on splicing due to this variant (Karow_2010_PMID:19951977). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.10
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.042	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.51	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.41
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.31		Loss of MoRF binding (P = 0.1008);
MVP		0.92
MPC		0.43
ClinPred		0.069	T
GERP RS		3.3
Varity_R		0.35
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.55
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: rs147652512; hg19: chr7-66460278; COSMIC: COSV55887716; COSMIC: COSV55887716;