19-51225221-C-T

Variant names:

• chr19-51225221-C-T
• rs12459419
• NM_001772.4:c.41C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: -0.191
• Publications: 162 publications found

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]

ENSG00000268595 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001772.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD33	NM_001772.4	MANE Select	c.41C>T	p.Ala14Val	missense	Exon 2 of 7	NP_001763.3
	CD33	NM_001177608.2		c.41C>T	p.Ala14Val	missense	Exon 2 of 7	NP_001171079.1
	CD33	NM_001082618.2		c.37+66C>T		intron	N/A	NP_001076087.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD33	ENST00000262262.5	TSL:1 MANE Select	c.41C>T	p.Ala14Val	missense	Exon 2 of 7	ENSP00000262262.3
	CD33	ENST00000391796.7	TSL:1	c.41C>T	p.Ala14Val	missense	Exon 2 of 7	ENSP00000375673.2
	CD33	ENST00000421133.6	TSL:1	c.37+66C>T		intron	N/A	ENSP00000410126.1

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

GnomAD2 exomes AF: 0.307 AC: 76894 AN: 250170 AF XY: 0.294

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 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

African (AFR) AF: 0.0756 AC: 2529 AN: 33456

American (AMR) AF: 0.547 AC: 24417 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 5902 AN: 26054

East Asian (EAS) AF: 0.191 AC: 7564 AN: 39690

South Asian (SAS) AF: 0.158 AC: 13579 AN: 86198

European-Finnish (FIN) AF: 0.362 AC: 19282 AN: 53238

Middle Eastern (MID) AF: 0.184 AC: 1059 AN: 5762

European-Non Finnish (NFE) AF: 0.322 AC: 357588 AN: 1111278

Other (OTH) AF: 0.270 AC: 16304 AN: 60340

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

African (AFR) AF: 0.0871 AC: 3619 AN: 41546

American (AMR) AF: 0.428 AC: 6536 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3472

East Asian (EAS) AF: 0.188 AC: 972 AN: 5166

South Asian (SAS) AF: 0.156 AC: 756 AN: 4832

European-Finnish (FIN) AF: 0.360 AC: 3804 AN: 10576

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21447 AN: 67936

Other (OTH) AF: 0.250 AC: 527 AN: 2110

Alfa AF: 0.264 Hom.: 5561

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.00023	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.19
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.043
Sift	Uncertain	0.029	D
Sift4G	Benign	0.13	T
Polyphen		0.48	P
Vest4		0.057
MPC		0.097
ClinPred		0.014	T
GERP RS		0.92
PromoterAI		-0.028	Neutral
Varity_R		0.031
gMVP		0.31
Mutation Taster		=99/1	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: rs12459419; hg19: chr19-51728477; COSMIC: COSV51800279; COSMIC: COSV51800279;