rs113993993

Variant names:

• chr7-66994210-A-G
• rs113993993
• NM_016038.4:c.258+2T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-66994210-A-G
• chr7-66994210-A-C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1 PS3 PP5_Very_Strong BS2_Supporting

The NM_016038.4(SBDS):​c.258+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,611,298 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000967787: PS3." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (10 hom.)
• Consequence: SBDS NM_016038.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:63 O:2
• Conservation: PhyloP100: 7.95
• Publications: 136 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: Orphanet, ClinGen
• 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 19 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.3, offset of 4, new splice context is: cggGTaaca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000967787: PS3.; SCV000996168: Functional studies suggest that the c.258+2 T>C variant affects the protein's cellular localization and motility (PMID: 21695142).; SCV002038567: In a functional study, Orelio et al. (2011) transiently transfected HeLa cells with GFP constructs containing full length or truncated protein due to the c.258+2T>C variant. The authors observed that the full-length protein was localized in both the nucleus and cytoplasm, while the truncated protein was mainly detected in the nucleus. The presence of the variant also affected nuclear import of SBDS proteins. PMID:21723144; SCV002072017: Functional studies have shown that this sequence change results in a non-expressed product and impairs SBDS function (PMID 17478638).; SCV002073333: Experimental studies have shown that this variant affects SBDS function Peretto L, et al., 2023.; SCV003853254: "functional studies suggest that the c.258+2 T>C variant affects the protein's cellular localization and motility (Orelio C et . al., 2011)."; SCV003922130: RT-PCR analysis performed on affected tissue shows evidence of altered splicing of exon 2, with an 8bp deletion, frameshift, and premature protein truncation (PMID: 12496757); in vitro assays suggest that the resulting prematurely truncated protein is unstable (PMID: 17478638).; SCV004813118: The variant allele was found at a frequency of 0.0039 in 251238 control chromosomes in the gnomAD database, including 2 homozygotes. However, due to the presence of a SBDS pseudogene, this frequency may be inaccurate, allowing no conclusion about variant significance. c.258+2T>C has been reported in the literature in many individuals affected with Shwachman-Diamond Syndrome 1 and is considered a common disease variant (e.g. Furutani_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36835434, 34758064). no; SCV005903753: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21695142).; SCV000321934: Published functional studies demonstrate that truncating variants, including c.258+2 T>C, may affect the protein's cellular localization and motility (Austin et al., 2005; Orelio et al., 2011).; SCV000898941: "In addition, functional studies have shown a deleterious effect of this variant (Orelio 2011 PMID:21695142)."; SCV004046223: Functional studies suggest that the c.258+2 T>C variant affects the protein's cellular localization and motility (PMID: 21695142).
• PP5: Variant 7-66994210-A-G is Pathogenic according to our data. Variant chr7-66994210-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.258+2T>C		splice_donor intron	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.258+2T>C		splice_donor intron	N/A	ENSP00000246868.2	Q9Y3A5
	SBDS	ENST00000697897.1		c.258+2T>C		splice_donor intron	N/A	ENSP00000513469.1	Q9Y3A5
	SBDS	ENST00000890817.1		c.258+2T>C		splice_donor intron	N/A	ENSP00000560876.1

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 151990 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00145

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00832

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00377

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00388 AC: 975 AN: 251238 AF XY: 0.00387

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00480

Gnomad FIN exome AF: 0.00958

Gnomad NFE exome AF: 0.00365

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00366 AC: 5343 AN: 1459192 Hom.: 10 Cov.: 32 AF XY: 0.00363 AC XY: 2635 AN XY: 726026

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00144 AC: 48 AN: 33446

American (AMR) AF: 0.00293 AC: 131 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26134

East Asian (EAS) AF: 0.00386 AC: 153 AN: 39602

South Asian (SAS) AF: 0.00331 AC: 285 AN: 86176

European-Finnish (FIN) AF: 0.00980 AC: 523 AN: 53352

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00356 AC: 3949 AN: 1109708

Other (OTH) AF: 0.00317 AC: 191 AN: 60312

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.00328 AC XY: 244 AN XY: 74354

African (AFR) AF: 0.00200 AC: 83 AN: 41540

American (AMR) AF: 0.00144 AC: 22 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00542 AC: 28 AN: 5170

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4830

European-Finnish (FIN) AF: 0.00832 AC: 88 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00377 AC: 256 AN: 67958

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00322 Hom.: 0

Bravo AF: 0.00301

EpiCase AF: 0.00349

EpiControl AF: 0.00433

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
37	-	-	Shwachman-Diamond syndrome 1 (38)
13	-	-	not provided (13)
4	-	-	Shwachman syndrome (4)
2	-	-	Aplastic anemia (2)
2	-	-	Aplastic anemia;C4692625:Shwachman-Diamond syndrome 1 (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	not specified (1)
1	-	-	SBDS-related disorder (1)
1	-	-	Splenomegaly;C0349588:Short stature;C0423224:Deeply set eye;C1290511:Agenesis of permanent teeth;C4551563:Microcephaly (1)
-	-	-	Aplastic anemia, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.0
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: 10
DS_DL_spliceai		0.93		Position offset: 2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs113993993;

hg19: chr7-66459197;

COSMIC: COSV55887021;

COSMIC: COSV55887021;