7-66995394-G-C

Variant names:

• chr7-66995394-G-C
• rs28942099
• NM_016038.4:c.24C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016038.4(SBDS):​c.24C>G​(p.Asn8Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N8S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SBDS NM_016038.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.16
• 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]

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

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.24C>G	p.Asn8Lys	missense	Exon 1 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.24C>G	p.Asn8Lys	missense	Exon 1 of 5	ENSP00000246868.2	Q9Y3A5
	SBDS	ENST00000697897.1		c.24C>G	p.Asn8Lys	missense	Exon 2 of 6	ENSP00000513469.1	Q9Y3A5
	SBDS	ENST00000890817.1		c.24C>G	p.Asn8Lys	missense	Exon 2 of 6	ENSP00000560876.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.032	D
Polyphen		0.97	D
Vest4		0.93
MutPred		0.83		Gain of MoRF binding (P = 0.0105)
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
PromoterAI		-0.0016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.81
Mutation Taster		=2/98	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

dbSNP: rs28942099; hg19: chr7-66460381;