19-51225385-A-T

Variant names:

• chr19-51225385-A-T
• rs2455069
• NM_001772.4:c.205A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001772.4(CD33):​c.205A>T​(p.Arg69Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69G) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: CD33 NM_001772.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.05
• Publications: 70 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06247589).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD33	NM_001772.4	MANE Select	c.205A>T	p.Arg69Trp	missense	Exon 2 of 7	NP_001763.3	Q546G0
	CD33	NM_001177608.2		c.205A>T	p.Arg69Trp	missense	Exon 2 of 7	NP_001171079.1	P20138-2
	CD33	NM_001082618.2		c.37+230A>T		intron	N/A	NP_001076087.1	P20138-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD33	ENST00000262262.5	TSL:1 MANE Select	c.205A>T	p.Arg69Trp	missense	Exon 2 of 7	ENSP00000262262.3	P20138-1
	CD33	ENST00000391796.7	TSL:1	c.205A>T	p.Arg69Trp	missense	Exon 2 of 7	ENSP00000375673.2	P20138-2
	CD33	ENST00000421133.6	TSL:1	c.37+230A>T		intron	N/A	ENSP00000410126.1	P20138-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151992 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome Cov.: 46

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151992 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74230

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41364

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 26725

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.089
DANN	Benign	0.57
DEOGEN2	Benign	0.10	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.0065	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		-5.0
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.025
Sift	Benign	0.22	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.099
MutPred		0.23		Gain of catalytic residue at P72 (P = 0.0244)
MVP		0.30
MPC		0.068
ClinPred		0.079	T
GERP RS		-7.0
PromoterAI		0.041	Neutral
Varity_R		0.25
gMVP		0.31
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2455069; hg19: chr19-51728641;