19-35527027-C-G

Variant names:

• chr19-35527027-C-G
• rs540224250
• NM_001166034.2:c.1255G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001166034.2(SBSN):​c.1255G>C​(p.Ala419Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000035 in 1,541,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A419S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: SBSN NM_001166034.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.618
• Publications: 0 publications found

Genes affected

SBSN (HGNC:24950): (suprabasin) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06971878).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166034.2. 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
	SBSN	NM_001166034.2	MANE Select	c.1255G>C	p.Ala419Pro	missense	Exon 1 of 4	NP_001159506.1	Q6UWP8-1
	SBSN	NM_198538.4		c.376-150G>C		intron	N/A	NP_940940.1	Q6UWP8-2
	SBSN	NM_001166035.2		c.375+880G>C		intron	N/A	NP_001159507.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBSN	ENST00000452271.7	TSL:1 MANE Select	c.1255G>C	p.Ala419Pro	missense	Exon 1 of 4	ENSP00000430242.1	Q6UWP8-1
	SBSN	ENST00000518157.1	TSL:1	c.376-150G>C		intron	N/A	ENSP00000428771.1	Q6UWP8-2
	SBSN	ENST00000588674.5	TSL:2	c.315+880G>C		intron	N/A	ENSP00000468646.2	K7ESC4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152056 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000269 AC: 4 AN: 148724 AF XY: 0.0000380

Gnomad AFR exome AF: 0.000121

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000333

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000374 AC: 52 AN: 1389710 Hom.: 0 Cov.: 64 AF XY: 0.0000423 AC XY: 29 AN XY: 685742

African (AFR) AF: 0.0000316 AC: 1 AN: 31598

American (AMR) AF: 0.0000560 AC: 2 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.0000839 AC: 3 AN: 35736

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000399 AC: 43 AN: 1078974

Other (OTH) AF: 0.0000172 AC: 1 AN: 58000

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41516

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.0000383 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.62
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.090
Sift	Benign	0.044	D
Sift4G	Benign	0.14	T
Vest4		0.18
MutPred		0.50		Loss of helix (P = 0.0795)
MVP		0.41
MPC		0.93
ClinPred		0.12	T
GERP RS		1.7
Varity_R		0.15
gMVP		0.067
Mutation Taster		=96/4	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: rs540224250; hg19: chr19-36017929;