rs186000847

Variant names:

• chr7-66994193-T-C
• rs186000847
• NM_016038.4:c.258+19A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016038.4(SBDS):​c.258+19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,204 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 31)
  • Exomes 𝑓: 0.014 (178 hom.)
• Consequence: SBDS NM_016038.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.33
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-66994193-T-C is Benign according to our data. Variant chr7-66994193-T-C is described in ClinVar as Benign. ClinVar VariationId is 260684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1654/152260) while in subpopulation NFE AF = 0.0174 (1186/68018). AF 95% confidence interval is 0.0166. There are 18 homozygotes in GnomAd4. There are 793 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

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+19A>G		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+19A>G		intron	N/A	ENSP00000246868.2	Q9Y3A5
	SBDS	ENST00000697897.1		c.258+19A>G		intron	N/A	ENSP00000513469.1	Q9Y3A5
	SBDS	ENST00000890817.1		c.258+19A>G		intron	N/A	ENSP00000560876.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1653 AN: 152142 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.0109 AC: 2729 AN: 251378 AF XY: 0.0107

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0141 AC: 20646 AN: 1460944 Hom.: 178 Cov.: 32 AF XY: 0.0138 AC XY: 10017 AN XY: 726816

African (AFR) AF: 0.00188 AC: 63 AN: 33462

American (AMR) AF: 0.00416 AC: 186 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 520 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00249 AC: 215 AN: 86248

European-Finnish (FIN) AF: 0.0199 AC: 1061 AN: 53294

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.0161 AC: 17918 AN: 1111260

Other (OTH) AF: 0.0112 AC: 677 AN: 60370

GnomAD4 genome AF: 0.0109 AC: 1654 AN: 152260 Hom.: 18 Cov.: 31 AF XY: 0.0107 AC XY: 793 AN XY: 74430

African (AFR) AF: 0.00253 AC: 105 AN: 41566

American (AMR) AF: 0.00327 AC: 50 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4834

European-Finnish (FIN) AF: 0.0176 AC: 187 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0174 AC: 1186 AN: 68018

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.0181 Hom.: 5

Bravo AF: 0.00917

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Aplastic anemia (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Shwachman-Diamond syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.049
DANN	Benign	0.63
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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: rs186000847; hg19: chr7-66459180; COSMIC: COSV55888886;