rs113993989

Variant names:

• chr7-66994329-G-A
• rs113993989
• NM_016038.4:c.141C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_016038.4(SBDS):​c.141C>T​(p.Leu47Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,612,664 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (36 hom.)
• Consequence: SBDS NM_016038.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.801
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 7-66994329-G-A is Benign according to our data. Variant chr7-66994329-G-A is described in ClinVar as Benign. ClinVar VariationId is 21536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.801 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00765 (1163/152066) while in subpopulation EAS AF = 0.0334 (173/5182). AF 95% confidence interval is 0.0293. There are 9 homozygotes in GnomAd4. There are 590 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.141C>T	p.Leu47Leu	synonymous	Exon 2 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.141C>T	p.Leu47Leu	synonymous	Exon 2 of 5	ENSP00000246868.2	Q9Y3A5
	SBDS	ENST00000697866.1		c.-178C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000513464.1	A0A8V8TLC6
	SBDS	ENST00000697897.1		c.141C>T	p.Leu47Leu	synonymous	Exon 3 of 6	ENSP00000513469.1	Q9Y3A5

Frequencies

GnomAD3 genomes AF: 0.00763 AC: 1159 AN: 151950 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00427

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.00831

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00653 AC: 1641 AN: 251316 AF XY: 0.00599

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0336

Gnomad FIN exome AF: 0.00343

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00419 AC: 6123 AN: 1460598 Hom.: 36 Cov.: 32 AF XY: 0.00422 AC XY: 3065 AN XY: 726670

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

African (AFR) AF: 0.0105 AC: 352 AN: 33432

American (AMR) AF: 0.00333 AC: 149 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26108

East Asian (EAS) AF: 0.0250 AC: 993 AN: 39652

South Asian (SAS) AF: 0.00584 AC: 503 AN: 86202

European-Finnish (FIN) AF: 0.00305 AC: 163 AN: 53356

Middle Eastern (MID) AF: 0.0144 AC: 83 AN: 5764

European-Non Finnish (NFE) AF: 0.00309 AC: 3438 AN: 1111012

Other (OTH) AF: 0.00630 AC: 380 AN: 60362

⚠️ 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: 0.00765 AC: 1163 AN: 152066 Hom.: 9 Cov.: 32 AF XY: 0.00794 AC XY: 590 AN XY: 74334

African (AFR) AF: 0.0121 AC: 504 AN: 41496

American (AMR) AF: 0.00426 AC: 65 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.0334 AC: 173 AN: 5182

South Asian (SAS) AF: 0.00832 AC: 40 AN: 4808

European-Finnish (FIN) AF: 0.00397 AC: 42 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00447 AC: 304 AN: 67956

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00478 Hom.: 2

Bravo AF: 0.00747

EpiCase AF: 0.00486

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Shwachman-Diamond syndrome 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.7
DANN	Benign	0.75
PhyloP100		-0.80
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs113993989; hg19: chr7-66459316; COSMIC: COSV55888348; COSMIC: COSV55888348;