Genetic Variant CD33:p.Tyr127His (chr19-51225559-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001772.4(CD33):c.379T>C(p.Tyr127His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,578,902 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0057 ( 22 hom., cov: 31)

Exomes 𝑓: 0.0033 ( 100 hom. )

Consequence

CD33
NM_001772.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.601

Publications

3 publications found

Variant links:

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]

CD33 links:

ENSG00000268595 (HGNC:):

ENSG00000268595 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037012994).

BP6

Variant 19-51225559-T-C is Benign according to our data. Variant chr19-51225559-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2650368.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD33	NM_001772.4 link	c.379T>C	p.Tyr127His	missense_variant	Exon 2 of 7	ENST00000262262.5	NP_001763.3	P20138-1Q546G0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD33	ENST00000262262.5 link	c.379T>C	p.Tyr127His	missense_variant	Exon 2 of 7	1	NM_001772.4	ENSP00000262262.3		P20138-1

Frequencies

GnomAD3 genomes

AF:

0.00574

AC:

873

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0631

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00703

AC:

1537

AN:

218580

AF XY:

0.00667

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.000130

Gnomad ASJ exome

AF:

0.000615

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0602

Gnomad NFE exome

AF:

0.00322

Gnomad OTH exome

AF:

0.00618

GnomAD4 exome

AF:

0.00329

AC:

4701

AN:

1426764

Hom.:

100

Cov.:

AF XY:

0.00319

AC XY:

2250

AN XY:

706326

show subpopulations

African (AFR)

AF:

0.000983

AC:

AN:

32568

American (AMR)

AF:

0.000121

AC:

AN:

41286

Ashkenazi Jewish (ASJ)

AF:

0.000736

AC:

AN:

23090

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39466

South Asian (SAS)

AF:

0.000138

AC:

AN:

79612

European-Finnish (FIN)

AF:

0.0561

AC:

2896

AN:

51666

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

0.00146

AC:

1601

AN:

1094688

Other (OTH)

AF:

0.00231

AC:

136

AN:

58818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

244

488

732

976

1220

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00573

AC:

872

AN:

152138

Hom.:

Cov.:

AF XY:

0.00789

AC XY:

587

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.000891

AC:

AN:

41510

American (AMR)

AF:

0.000262

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0631

AC:

669

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00222

AC:

151

AN:

67990

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00273

Hom.:

Bravo

AF:

0.00114

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00583

AC:

707

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CD33: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.31

.;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.10

T;T

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.5

L;L

PhyloP100

0.60

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.040

Sift

Benign

0.14

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.087

.;B

Vest4

0.13

MVP

0.72

MPC

0.12

ClinPred

0.0033

GERP RS

1.9

PromoterAI

0.0044

Neutral

(source)

Varity_R

0.22

gMVP

0.28

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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chr19-51225559-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over