rs3746731

Positions:

• chr20-23084572-G-A
• chr20-23084572-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012072.4(CD93):​c.1621C>T​(p.Pro541Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 1,613,292 control chromosomes in the GnomAD database, including 250,691 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.51 (20646 hom., cov: 34)
  • Exomes 𝑓: 0.56 (230045 hom.)
• Consequence: CD93 NM_012072.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.55

Genes affected

CD93 (HGNC:15855): (CD93 molecule) The protein encoded by this gene is a cell-surface glycoprotein and type I membrane protein that was originally identified as a myeloid cell-specific marker. The encoded protein was once thought to be a receptor for C1q, but now is thought to instead be involved in intercellular adhesion and in the clearance of apoptotic cells. The intracellular cytoplasmic tail of this protein has been found to interact with moesin, a protein known to play a role in linking transmembrane proteins to the cytoskeleton and in the remodelling of the cytoskeleton. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.35512455E-5).
• BP6: Variant 20-23084572-G-A is Benign according to our data. Variant chr20-23084572-G-A is described in ClinVar as [Benign]. Clinvar id is 2688535.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD93	NM_012072.4	c.1621C>T	p.Pro541Ser	missense_variant	1/2	ENST00000246006.5	NP_036204.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD93	ENST00000246006.5	c.1621C>T	p.Pro541Ser	missense_variant	1/2	1	NM_012072.4	ENSP00000246006.4

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77464 AN: 151982 Hom.: 20623 Cov.: 34

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.558

GnomAD3 exomes AF: 0.566 AC: 141714 AN: 250180 Hom.: 41251 AF XY: 0.572 AC XY: 77426 AN XY: 135470

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.650

Gnomad ASJ exome AF: 0.645

Gnomad EAS exome AF: 0.641

Gnomad SAS exome AF: 0.642

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.561

Gnomad OTH exome AF: 0.604

GnomAD4 exome AF: 0.558 AC: 815062 AN: 1461192 Hom.: 230045 Cov.: 55 AF XY: 0.562 AC XY: 408280 AN XY: 726904

Gnomad4 AFR exome AF: 0.372

Gnomad4 AMR exome AF: 0.646

Gnomad4 ASJ exome AF: 0.645

Gnomad4 EAS exome AF: 0.662

Gnomad4 SAS exome AF: 0.644

Gnomad4 FIN exome AF: 0.394

Gnomad4 NFE exome AF: 0.554

Gnomad4 OTH exome AF: 0.563

GnomAD4 genome AF: 0.510 AC: 77532 AN: 152100 Hom.: 20646 Cov.: 34 AF XY: 0.504 AC XY: 37494 AN XY: 74360

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.593

Gnomad4 ASJ AF: 0.643

Gnomad4 EAS AF: 0.629

Gnomad4 SAS AF: 0.662

Gnomad4 FIN AF: 0.377

Gnomad4 NFE AF: 0.562

Gnomad4 OTH AF: 0.562

Alfa AF: 0.566 Hom.: 37808

Bravo AF: 0.523

TwinsUK AF: 0.556 AC: 2063

ALSPAC AF: 0.543 AC: 2091

ESP6500AA AF: 0.367 AC: 1618

ESP6500EA AF: 0.567 AC: 4873

ExAC AF: 0.561 AC: 68172

Asia WGS AF: 0.630 AC: 2192 AN: 3478

EpiCase AF: 0.582

EpiControl AF: 0.586

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 76. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.4
DANN	Benign	0.90
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.000014	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.14
Sift	Benign	0.36	T
Sift4G	Benign	0.36	T
Polyphen		0.19	B
Vest4		0.028
MPC		0.13
ClinPred		0.012	T
GERP RS		3.8
Varity_R		0.035
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs3746731; hg19: chr20-23065209; COSMIC: COSV55664149;