19-51225590-A-G

Position:

• chr19-51225590-A-G

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.410A>G​(p.His137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,555,428 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (19 hom., cov: 31)
  • Exomes 𝑓: 0.00093 (17 hom.)
• Consequence: CD33 NM_001772.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.03

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=0.006160289).
• BP6: Variant 19-51225590-A-G is Benign according to our data. Variant chr19-51225590-A-G is described in ClinVar as [Benign]. Clinvar id is 775425.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 = 0.00897 (1366/152268) while in subpopulation AFR AF= 0.0312 (1297/41534). AF 95% confidence interval is 0.0298. There are 19 homozygotes in gnomad4. There are 630 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD33	NM_001772.4	c.410A>G	p.His137Arg	missense_variant	2/7	ENST00000262262.5	NP_001763.3
LOC107985327	XR_007067309.1	n.232-30930T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD33	ENST00000262262.5	c.410A>G	p.His137Arg	missense_variant	2/7	1	NM_001772.4	ENSP00000262262	P2

Frequencies

GnomAD3 genomes AF: 0.00897 AC: 1365 AN: 152150 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00270 AC: 547 AN: 202796 Hom.: 12 AF XY: 0.00205 AC XY: 220 AN XY: 107296

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.000194

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000498

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000746

Gnomad OTH exome AF: 0.00128

GnomAD4 exome AF: 0.000934 AC: 1310 AN: 1403160 Hom.: 17 Cov.: 33 AF XY: 0.000832 AC XY: 575 AN XY: 691414

Gnomad4 AFR exome AF: 0.0322

Gnomad4 AMR exome AF: 0.00213

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000525

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000693

Gnomad4 OTH exome AF: 0.00203

GnomAD4 genome AF: 0.00897 AC: 1366 AN: 152268 Hom.: 19 Cov.: 31 AF XY: 0.00846 AC XY: 630 AN XY: 74474

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00177 Hom.: 3

Bravo AF: 0.0102

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00277 AC: 334

Asia WGS AF: 0.00231 AC: 8 AN: 3478

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	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.011
DANN	Benign	0.17
DEOGEN2	Benign	0.26	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.00030	T;T
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Benign	0.034
Sift	Benign	0.36	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0070	.;B
Vest4		0.040
MVP		0.42
MPC		0.079
ClinPred		0.035	T
GERP RS		-4.6
Varity_R		0.46
gMVP		0.14

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: rs61736473; hg19: chr19-51728846;