19-51225221-C-T

Position:

• chr19-51225221-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001772.4(CD33):​c.41C>T​(p.Ala14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,612,814 control chromosomes in the GnomAD database, including 79,734 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.25 (6052 hom., cov: 32)
  • Exomes 𝑓: 0.31 (73682 hom.)
• Consequence: CD33 NM_001772.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.191

Genes affected

CD33 (HGNC:1659): (CD33 molecule) Enables protein phosphatase binding activity and sialic acid binding activity. Involved in several processes, including negative regulation of cytokine production; negative regulation of monocyte activation; and positive regulation of protein tyrosine phosphatase activity. Located in several cellular components, including Golgi apparatus; external side of plasma membrane; and peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

LOC107985327 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2751093E-4).
• BP6: Variant 19-51225221-C-T is Benign according to our data. Variant chr19-51225221-C-T is described in ClinVar as [Benign]. Clinvar id is 1275129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD33	NM_001772.4	c.41C>T	p.Ala14Val	missense_variant	2/7	ENST00000262262.5	NP_001763.3
LOC107985327	XR_007067309.1	n.232-30561G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD33	ENST00000262262.5	c.41C>T	p.Ala14Val	missense_variant	2/7	1	NM_001772.4	ENSP00000262262	P2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38597 AN: 152014 Hom.: 6040 Cov.: 32

Gnomad AFR AF: 0.0872

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.252

GnomAD3 exomes AF: 0.307 AC: 76894 AN: 250170 Hom.: 14417 AF XY: 0.294 AC XY: 39783 AN XY: 135206

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.561

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.184

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.320

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.307 AC: 448224 AN: 1460682 Hom.: 73682 Cov.: 52 AF XY: 0.301 AC XY: 218666 AN XY: 726522

Gnomad4 AFR exome AF: 0.0756

Gnomad4 AMR exome AF: 0.547

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.191

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.362

Gnomad4 NFE exome AF: 0.322

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.254 AC: 38618 AN: 152132 Hom.: 6052 Cov.: 32 AF XY: 0.258 AC XY: 19208 AN XY: 74380

Gnomad4 AFR AF: 0.0871

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.250

Alfa AF: 0.260 Hom.: 3374

Bravo AF: 0.255

TwinsUK AF: 0.324 AC: 1200

ALSPAC AF: 0.336 AC: 1296

ESP6500AA AF: 0.0933 AC: 411

ESP6500EA AF: 0.301 AC: 2585

ExAC AF: 0.293 AC: 35573

Asia WGS AF: 0.169 AC: 591 AN: 3478

EpiCase AF: 0.302

EpiControl AF: 0.299

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	This variant is associated with the following publications: (PMID: 25762156, 24381305, 26621708, 23946390, 30917570) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	.;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.00023	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.043
Sift	Uncertain	0.029	D;T
Sift4G	Benign	0.13	T;T
Polyphen		0.48	.;P
Vest4		0.057
MPC		0.097
ClinPred		0.014	T
GERP RS		0.92
Varity_R		0.031
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs12459419; hg19: chr19-51728477; COSMIC: COSV51800279; COSMIC: COSV51800279;