chr7-66994286-TA-AG

Variant names:

• chr7-66994286-TA-AG
• rs113993991
• NM_016038.4:c.183_184delTAinsCT

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_016038.4(SBDS):​c.183_184delTAinsCT​(p.Lys62*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000740931: A functional study in yeast cells found that this mutation resulted in complete loss of function (Shammas C et al. J. Biol. Chem., 2005 May" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S61S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SBDS NM_016038.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 7.01
• Publications: 46 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000740931: A functional study in yeast cells found that this mutation resulted in complete loss of function (Shammas C et al. J. Biol. Chem., 2005 May;280:19221-9).; SCV003924240: This variant creates a premature stop at this codon which results in an abnormal protein, and has been experimentally confirmed to result in a loss of protein function due to impaired cytoplasmic localization in vitro (Shammas 2005 PMID:15701631; Orelio 2011 PMID:21695142).
• PP5: Variant 7-66994286-TA-AG is Pathogenic according to our data. Variant chr7-66994286-TA-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 3195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.183_184delTAinsCT	p.Lys62*	stop_gained	N/A	NP_057122.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBDS	ENST00000246868.7	TSL:1 MANE Select	c.183_184delTAinsCT	p.Lys62*	stop_gained	N/A	ENSP00000246868.2	Q9Y3A5
	SBDS	ENST00000697897.1		c.183_184delTAinsCT	p.Lys62*	stop_gained	N/A	ENSP00000513469.1	Q9Y3A5
	SBDS	ENST00000890817.1		c.183_184delTAinsCT	p.Lys62*	stop_gained	N/A	ENSP00000560876.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Shwachman-Diamond syndrome 1 (7)
5	-	-	not provided (5)
3	-	-	Aplastic anemia;C4692625:Shwachman-Diamond syndrome 1 (3)
2	-	-	Shwachman syndrome (2)
1	-	-	Aplastic anemia (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	SBDS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113993991; hg19: chr7-66459273;