rs147652512

Variant names:

• chr7-66995291-C-A
• rs147652512
• NM_016038.4:c.127G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-66995291-C-A
• chr7-66995291-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_016038.4(SBDS):​c.127G>T​(p.Val43Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,556 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: SBDS NM_016038.4 missense, splice_region
• Scores: Splicing: ADA: 0.7986
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.73
• Publications: 7 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]

TYW1 (HGNC:25598): (tRNA-yW synthesizing protein 1 homolog) Wybutosine (yW) is a hypermodified guanosine found in phenylalanine tRNA adjacent to the anticodon that stabilizes codon-anticodon interactions in the ribosome. In yeast, the homolog of this gene is essential for the synthesis of wybutosine. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04228115).
• BP6: Variant 7-66995291-C-A is Benign according to our data. Variant chr7-66995291-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378498.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.127G>T	p.Val43Leu	missense splice_region	Exon 1 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.127G>T	p.Val43Leu	missense splice_region	Exon 1 of 5	ENSP00000246868.2	Q9Y3A5
	SBDS	ENST00000697866.1		c.-384G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000513464.1	A0A8V8TLC6
	SBDS	ENST00000697897.1		c.127G>T	p.Val43Leu	missense splice_region	Exon 2 of 6	ENSP00000513469.1	Q9Y3A5

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00117 AC: 293 AN: 251058 AF XY: 0.00113

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00146 AC: 2138 AN: 1461188 Hom.: 2 Cov.: 31 AF XY: 0.00147 AC XY: 1068 AN XY: 726906

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

African (AFR) AF: 0.000179 AC: 6 AN: 33462

American (AMR) AF: 0.000470 AC: 21 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86232

European-Finnish (FIN) AF: 0.000655 AC: 35 AN: 53402

Middle Eastern (MID) AF: 0.000366 AC: 2 AN: 5464

European-Non Finnish (NFE) AF: 0.00179 AC: 1985 AN: 1111756

Other (OTH) AF: 0.00104 AC: 63 AN: 60330

⚠️ 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: 0.000991 AC: 151 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000913 AC XY: 68 AN XY: 74516

African (AFR) AF: 0.000192 AC: 8 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000839

ExAC AF: 0.00151 AC: 183

EpiCase AF: 0.00158

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.10
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.042	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.41
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.31		Loss of MoRF binding (P = 0.1008)
MVP		0.92
MPC		0.43
ClinPred		0.069	T
GERP RS		3.3
PromoterAI		0.012	Neutral
Varity_R		0.35
gMVP		0.47
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.55
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: rs147652512; hg19: chr7-66460278; COSMIC: COSV55887716; COSMIC: COSV55887716;