rs35112940

Variant names:

• chr19-51235662-G-A
• rs35112940
• NM_001772.4:c.910G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001772.4(CD33):​c.910G>A​(p.Gly304Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,612,898 control chromosomes in the GnomAD database, including 31,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1997 hom., cov: 31)
  • Exomes 𝑓: 0.19 (29508 hom.)
• Consequence: CD33 NM_001772.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.577
• Publications: 43 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 -16 ACMG points.

• BP6: Variant 19-51235662-G-A is Benign according to our data. Variant chr19-51235662-G-A is described in ClinVar as Benign. ClinVar VariationId is 1237638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD33	NM_001772.4	MANE Select	c.910G>A	p.Gly304Arg	missense	Exon 6 of 7	NP_001763.3	Q546G0
	CD33	NM_001177608.2		c.910G>A	p.Gly304Arg	missense	Exon 6 of 7	NP_001171079.1	P20138-2
	CD33	NM_001082618.2		c.529G>A	p.Gly177Arg	missense	Exon 5 of 6	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.910G>A	p.Gly304Arg	missense	Exon 6 of 7	ENSP00000262262.3	P20138-1
	CD33	ENST00000391796.7	TSL:1	c.910G>A	p.Gly304Arg	missense	Exon 6 of 7	ENSP00000375673.2	P20138-2
	CD33	ENST00000421133.6	TSL:1	c.529G>A	p.Gly177Arg	missense	Exon 5 of 6	ENSP00000410126.1	P20138-3

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21505 AN: 151980 Hom.: 1997 Cov.: 31

Gnomad AFR AF: 0.0466

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0431

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.147 AC: 36548 AN: 248748 AF XY: 0.147

Gnomad AFR exome AF: 0.0432

Gnomad AMR exome AF: 0.0772

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.267

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.190 AC: 277033 AN: 1460800 Hom.: 29508 Cov.: 33 AF XY: 0.185 AC XY: 134774 AN XY: 726622

African (AFR) AF: 0.0405 AC: 1357 AN: 33476

American (AMR) AF: 0.0815 AC: 3638 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3696 AN: 26106

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39688

South Asian (SAS) AF: 0.0491 AC: 4222 AN: 86052

European-Finnish (FIN) AF: 0.262 AC: 13996 AN: 53326

Middle Eastern (MID) AF: 0.106 AC: 611 AN: 5766

European-Non Finnish (NFE) AF: 0.216 AC: 239816 AN: 1111396

Other (OTH) AF: 0.161 AC: 9689 AN: 60348

GnomAD4 genome AF: 0.141 AC: 21498 AN: 152098 Hom.: 1997 Cov.: 31 AF XY: 0.141 AC XY: 10460 AN XY: 74348

African (AFR) AF: 0.0464 AC: 1925 AN: 41516

American (AMR) AF: 0.105 AC: 1612 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 443 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.0438 AC: 211 AN: 4818

European-Finnish (FIN) AF: 0.261 AC: 2754 AN: 10556

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.207 AC: 14083 AN: 67956

Other (OTH) AF: 0.140 AC: 295 AN: 2102

Alfa AF: 0.174 Hom.: 6712

Bravo AF: 0.128

TwinsUK AF: 0.222 AC: 822

ALSPAC AF: 0.229 AC: 883

ESP6500AA AF: 0.0542 AC: 239

ESP6500EA AF: 0.198 AC: 1704

ExAC AF: 0.148 AC: 17960

Asia WGS AF: 0.0230 AC: 83 AN: 3478

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	0.11
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.6
DANN	Benign	0.79
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.58
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.052
Sift	Benign	0.14	T
Sift4G	Benign	0.36	T
Polyphen		0.14	B
Vest4		0.024
MutPred		0.12		Gain of MoRF binding (P = 0.0143)
MPC		0.077
ClinPred		0.0028	T
GERP RS		0.28
Varity_R		0.061
gMVP		0.093
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35112940; hg19: chr19-51738917; COSMIC: COSV51805814; COSMIC: COSV51805814;