Genetic Variant CD320:p.Gly4Asp (chr19-8308280-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_016579.4(CD320):c.11G>A(p.Gly4Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,587,356 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 14 hom. )

Consequence

CD320
NM_016579.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.122

Variant links:

Genes affected

CD320 (HGNC:16692): (CD320 molecule) This gene encodes the transcobalamin receptor that is expressed at the cell surface. It mediates the cellular uptake of transcobalamin bound cobalamin (vitamin B12), and is involved in B-cell proliferation and immunoglobulin secretion. Mutations in this gene are associated with methylmalonic aciduria. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2011]

CD320 links:

ENSG00000167774 (HGNC:):

ENSG00000167774 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069682).

BP6

Variant 19-8308280-C-T is Benign according to our data. Variant chr19-8308280-C-T is described in ClinVar as [Benign]. Clinvar id is 770805.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD320	NM_016579.4 link	c.11G>A	p.Gly4Asp	missense_variant	Exon 1 of 5	ENST00000301458.10	NP_057663.1	Q9NPF0-1
CD320	NM_001165895.2 link	c.11G>A	p.Gly4Asp	missense_variant	Exon 1 of 4		NP_001159367.1	Q9NPF0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD320	ENST00000301458.10 link	c.11G>A	p.Gly4Asp	missense_variant	Exon 1 of 5	1	NM_016579.4	ENSP00000301458.4		Q9NPF0-1
ENSG00000167774	ENST00000598884.1 link	n.*220G>A		downstream_gene_variant		4		ENSP00000470609.1

Frequencies

GnomAD3 genomes

AF:

0.00259

AC:

395

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00527

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00379

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00229

AC:

464

AN:

202596

AF XY:

0.00232

show subpopulations

Gnomad AFR exome

AF:

0.000817

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.00567

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00505

Gnomad NFE exome

AF:

0.00311

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00344

AC:

4937

AN:

1435000

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

2410

AN XY:

713414

show subpopulations

African (AFR)

AF:

0.000515

AC:

AN:

32988

American (AMR)

AF:

0.00122

AC:

AN:

43338

Ashkenazi Jewish (ASJ)

AF:

0.00752

AC:

194

AN:

25784

East Asian (EAS)

AF:

0.00

AC:

AN:

38936

South Asian (SAS)

AF:

0.000926

AC:

AN:

84188

European-Finnish (FIN)

AF:

0.00537

AC:

208

AN:

38716

Middle Eastern (MID)

AF:

0.00472

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00375

AC:

4143

AN:

1105662

Other (OTH)

AF:

0.00364

AC:

217

AN:

59662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

289

578

867

1156

1445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00259

AC:

395

AN:

152356

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

179

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41590

American (AMR)

AF:

0.000850

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00952

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00527

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00379

AC:

258

AN:

68042

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00274

Hom.:

Bravo

AF:

0.00206

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000256

AC:

ESP6500EA

AF:

0.00283

AC:

ExAC

AF:

0.00231

AC:

273

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Methylmalonic acidemia due to transcobalamin receptor defect

Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

.;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

0.0070

T;T

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

1.6

L;L

PhyloP100

0.12

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.15

N;N

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.97

.;D

Vest4

0.17

MVP

0.97

MPC

0.60

ClinPred

0.077

GERP RS

2.0

PromoterAI

-0.0092

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.17

gMVP

0.83

Mutation Taster

=99/1

polymorphism

(source)

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

Loading publications...

19-8308280-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over