rs762817366

Variant names:

• chr19-8302537-G-A
• rs762817366
• NM_016579.4:c.775C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-8302537-G-A
• chr19-8302537-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016579.4(CD320):​c.775C>T​(p.Leu259Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: CD320 NM_016579.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.198
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• methylmalonic acidemia due to transcobalamin receptor defect

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1785335).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016579.4. 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
	CD320	NM_016579.4	MANE Select	c.775C>T	p.Leu259Phe	missense	Exon 5 of 5	NP_057663.1	Q9NPF0-1
	CD320	NM_001165895.2		c.649C>T	p.Leu217Phe	missense	Exon 4 of 4	NP_001159367.1	Q9NPF0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD320	ENST00000301458.10	TSL:1 MANE Select	c.775C>T	p.Leu259Phe	missense	Exon 5 of 5	ENSP00000301458.4	Q9NPF0-1
	CD320	ENST00000596002.5	TSL:1	n.*1063C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000471773.1	M0R1C4
	CD320	ENST00000596002.5	TSL:1	n.*1063C>T		3_prime_UTR	Exon 5 of 5	ENSP00000471773.1	M0R1C4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251150 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 727162

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111936

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.20
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.016	D
Polyphen		0.98	D
Vest4		0.20
MutPred		0.36		Loss of helix (P = 0.0068)
MVP		0.97
MPC		0.20
ClinPred		0.17	T
GERP RS		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.33
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs762817366; hg19: chr19-8367421;