7-66995291-C-A

Position:

chr7-66995291-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_StrongBP6BS2_Supporting

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:3B:1

Conservation

PhyloP100: 2.73

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:

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]

TYW1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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

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: {Likely_benign=1, Uncertain_significance=2}. Variant chr7-66995291-C-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SBDS	NM_016038.4 linkuse as main transcript	c.127G>T	p.Val43Leu	missense_variant, splice_region_variant	1/5	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.127G>T	p.Val43Leu	missense_variant, splice_region_variant	1/5	1	NM_016038.4	ENSP00000246868	P1

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152250

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00113

AC XY:

153

AN XY:

135814

show subpopulations

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.:

Cov.:

AF XY:

0.00147

AC XY:

1068

AN XY:

726906

show subpopulations

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.:

Cov.:

AF XY:

0.000913

AC XY:

AN XY:

74516

show subpopulations

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.:

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:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2024	Observed with a pathogenic variant on the opposite allele (in trans) in a patient with Diamond-Blackfan anemia in published literature (PMID: 26136524, 31839986); Observed in the heterozygous state with no second SBDS variant in patients with refractory cytopenia or suspected Shwachman-Diamond syndrome (PMID: 19951977, 34151701, Thomassen JC et al., 2016); 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, 36835434, 19951977) -
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

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

Eigen

Benign

-0.10

Eigen_PC

Benign

0.026

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.042

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.51

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.41

Sift

Benign

0.12

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.16

MutPred

0.31

Loss of MoRF binding (P = 0.1008);

MVP

0.92

MPC

0.43

ClinPred

0.069

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

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