chr7-66988489-A-G

Variant names:

• chr7-66988489-A-G
• rs79344818
• NM_016038.4:c.635T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016038.4(SBDS):​c.635T>C​(p.Ile212Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0326 in 1,613,618 control chromosomes in the GnomAD database, including 1,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I212S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (78 hom., cov: 32)
  • Exomes 𝑓: 0.033 (985 hom.)
• Consequence: SBDS NM_016038.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 6.52
• Publications: 20 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_016038.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.008209795).
• BP6: Variant 7-66988489-A-G is Benign according to our data. Variant chr7-66988489-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0256 (3903/152286) while in subpopulation AMR AF = 0.0399 (610/15282). AF 95% confidence interval is 0.0373. There are 78 homozygotes in GnomAd4. There are 1840 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 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.635T>C	p.Ile212Thr	missense	Exon 5 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.635T>C	p.Ile212Thr	missense	Exon 5 of 5	ENSP00000246868.2	Q9Y3A5
	SBDS	ENST00000697897.1		c.635T>C	p.Ile212Thr	missense	Exon 6 of 6	ENSP00000513469.1	Q9Y3A5
	SBDS	ENST00000890817.1		c.635T>C	p.Ile212Thr	missense	Exon 6 of 6	ENSP00000560876.1

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3903 AN: 152168 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00883

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0400

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.00809

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0366

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0253 AC: 6356 AN: 251168 AF XY: 0.0253

Gnomad AFR exome AF: 0.00664

Gnomad AMR exome AF: 0.0293

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00943

Gnomad NFE exome AF: 0.0363

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0333 AC: 48623 AN: 1461332 Hom.: 985 Cov.: 31 AF XY: 0.0327 AC XY: 23761 AN XY: 727010

African (AFR) AF: 0.00597 AC: 200 AN: 33480

American (AMR) AF: 0.0296 AC: 1325 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 971 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0119 AC: 1024 AN: 86256

European-Finnish (FIN) AF: 0.00933 AC: 495 AN: 53080

Middle Eastern (MID) AF: 0.0365 AC: 209 AN: 5724

European-Non Finnish (NFE) AF: 0.0382 AC: 42471 AN: 1111868

Other (OTH) AF: 0.0319 AC: 1925 AN: 60372

GnomAD4 genome AF: 0.0256 AC: 3903 AN: 152286 Hom.: 78 Cov.: 32 AF XY: 0.0247 AC XY: 1840 AN XY: 74482

African (AFR) AF: 0.00881 AC: 366 AN: 41552

American (AMR) AF: 0.0399 AC: 610 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4826

European-Finnish (FIN) AF: 0.00809 AC: 86 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0366 AC: 2490 AN: 68020

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0329 Hom.: 211

Bravo AF: 0.0277

TwinsUK AF: 0.0359 AC: 133

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0388 AC: 334

ExAC AF: 0.0248 AC: 3006

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0430

EpiControl AF: 0.0419

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	5	Shwachman-Diamond syndrome 1 (5)
-	-	2	not provided (2)
-	-	1	Aplastic anemia (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0082	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.017	D
Polyphen		0.15	B
Vest4		0.55
MPC		0.73
ClinPred		0.063	T
GERP RS		2.6
Varity_R		0.39
gMVP		0.76
Mutation Taster		=85/15	polymorphism (auto)

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: rs79344818; hg19: chr7-66453476; COSMIC: COSV55886995;