Genetic Variant NM_016038.4:c.629G>A (chr7-66988495-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_016038.4(SBDS):c.629G>A(p.Cys210Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C210F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SBDS
NM_016038.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.24

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Shwachman-Diamond syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Shwachman-Diamond syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

SBDS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

PP5

Variant 7-66988495-C-T is Pathogenic according to our data. Variant chr7-66988495-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1339526.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016038.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBDS	NM_016038.4	MANE Select	c.629G>A	p.Cys210Tyr	missense	Exon 5 of 5	NP_057122.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SBDS	ENST00000246868.7	TSL:1 MANE Select	c.629G>A	p.Cys210Tyr	missense	Exon 5 of 5	ENSP00000246868.2	Q9Y3A5
SBDS	ENST00000697897.1		c.629G>A	p.Cys210Tyr	missense	Exon 6 of 6	ENSP00000513469.1	Q9Y3A5
SBDS	ENST00000890817.1		c.629G>A	p.Cys210Tyr	missense	Exon 6 of 6	ENSP00000560876.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Shwachman-Diamond syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.8

PhyloP100

5.2

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.81

Sift

Benign

0.065

Sift4G

Benign

0.28

Polyphen

0.95

Vest4

0.84

MutPred

0.59

Gain of sheet (P = 0.1208)

MVP

0.99

MPC

1.6

ClinPred

0.99

GERP RS

5.0

Varity_R

0.92

gMVP

0.78

Mutation Taster

=32/68

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over