NM_016038.4:c.739G>A

Variant names:

• chr7-66988385-C-T
• NM_016038.4:c.739G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016038.4(SBDS):​c.739G>A​(p.Glu247Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SBDS NM_016038.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.739G>A	p.Glu247Lys	missense	Exon 5 of 5	NP_057122.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBDS	ENST00000246868.7	TSL:1 MANE Select	c.739G>A	p.Glu247Lys	missense	Exon 5 of 5	ENSP00000246868.2	Q9Y3A5
	SBDS	ENST00000697897.1		c.739G>A	p.Glu247Lys	missense	Exon 6 of 6	ENSP00000513469.1	Q9Y3A5
	SBDS	ENST00000890817.1		c.739G>A	p.Glu247Lys	missense	Exon 6 of 6	ENSP00000560876.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.048	D
Polyphen		0.97	D
Vest4		0.58
MutPred		0.19		Gain of ubiquitination at E247 (P = 0.009)
MVP		0.99
MPC		1.2
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.72
gMVP		0.50
Mutation Taster		=23/77	disease causing

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

Other links and lift over

hg19: chr7-66453372;