19-51225311-T-C

Position:

• chr19-51225311-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001772.4(CD33):​c.131T>C​(p.Phe44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,614,156 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (7 hom.)
• Consequence: CD33 NM_001772.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.396

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=0.0026769042).
• BP6: Variant 19-51225311-T-C is Benign according to our data. Variant chr19-51225311-T-C is described in ClinVar as [Benign]. Clinvar id is 777507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00818 (1245/152282) while in subpopulation AFR AF= 0.0276 (1148/41542). AF 95% confidence interval is 0.0263. There are 15 homozygotes in gnomad4. There are 606 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD33	NM_001772.4	c.131T>C	p.Phe44Ser	missense_variant	2/7	ENST00000262262.5	NP_001763.3
LOC107985327	XR_007067309.1	n.232-30651A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD33	ENST00000262262.5	c.131T>C	p.Phe44Ser	missense_variant	2/7	1	NM_001772.4	ENSP00000262262	P2

Frequencies

GnomAD3 genomes AF: 0.00818 AC: 1244 AN: 152164 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00224 AC: 563 AN: 251468 Hom.: 6 AF XY: 0.00189 AC XY: 257 AN XY: 135906

Gnomad AFR exome AF: 0.0260

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000900 AC: 1315 AN: 1461874 Hom.: 7 Cov.: 34 AF XY: 0.000815 AC XY: 593 AN XY: 727236

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00818 AC: 1245 AN: 152282 Hom.: 15 Cov.: 32 AF XY: 0.00814 AC XY: 606 AN XY: 74474

Gnomad4 AFR AF: 0.0276

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00230 Hom.: 5

Bravo AF: 0.00912

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00270 AC: 328

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.41
DANN	Benign	0.26
DEOGEN2	Benign	0.069	.;T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.027	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.89	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.16	N;N
REVEL	Benign	0.034
Sift	Benign	0.96	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.062
MVP		0.14
MPC		0.11
ClinPred		0.00070	T
GERP RS		-7.3
Varity_R		0.16
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs61736469; hg19: chr19-51728567;