rs250511

chr19-8302620-T-Achr19-8302620-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016579.4(CD320):c.707-15A>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0954 in 1,611,924 control chromosomes in the GnomAD database, including 7,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (661 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7069 hom.)
• Consequence: CD320 NM_016579.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-8302620-T-A is Benign according to our data. Variant chr19-8302620-T-A is described in ClinVar as [Benign]. Clinvar id is 136685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD320	NM_016579.4	c.707-15A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000301458.10
CD320	NM_001165895.2	c.581-15A>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD320	ENST00000301458.10	c.707-15A>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_016579.4	P1
CD320	ENST00000596002.5	c.*995-15A>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1
CD320	ENST00000537716.6	c.581-15A>T		splice_polypyrimidine_tract_variant, intron_variant		2
CD320	ENST00000599573.1	c.*307-15A>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0883 AC: 13411 AN: 151938 Hom.: 662 Cov.: 32

Gnomad AFR AF: 0.0753

Gnomad AMI AF: 0.0826

Gnomad AMR AF: 0.0664

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.0825

Gnomad FIN AF: 0.0858

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0938

Gnomad OTH AF: 0.0948

GnomAD3 exomes AF: 0.0886 AC: 22092 AN: 249236 Hom.: 1152 AF XY: 0.0902 AC XY: 12160 AN XY: 134746

Gnomad AFR exome AF: 0.0750

Gnomad AMR exome AF: 0.0414

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.138

Gnomad SAS exome AF: 0.0780

Gnomad FIN exome AF: 0.0895

Gnomad NFE exome AF: 0.0936

Gnomad OTH exome AF: 0.0922

GnomAD4 exome AF: 0.0962 AC: 140429 AN: 1459868 Hom.: 7069 Cov.: 34 AF XY: 0.0962 AC XY: 69850 AN XY: 725918

Gnomad4 AFR exome AF: 0.0809

Gnomad4 AMR exome AF: 0.0443

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.0774

Gnomad4 FIN exome AF: 0.0901

Gnomad4 NFE exome AF: 0.0972

Gnomad4 OTH exome AF: 0.0997

GnomAD4 genome AF: 0.0883 AC: 13419 AN: 152056 Hom.: 661 Cov.: 32 AF XY: 0.0872 AC XY: 6481 AN XY: 74326

Gnomad4 AFR AF: 0.0754

Gnomad4 AMR AF: 0.0662

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.0830

Gnomad4 FIN AF: 0.0858

Gnomad4 NFE AF: 0.0938

Gnomad4 OTH AF: 0.0948

Alfa AF: 0.0682 Hom.: 119

Bravo AF: 0.0867

Asia WGS AF: 0.0960 AC: 332 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Methylmalonic acidemia due to transcobalamin receptor defect Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.15
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs250511; hg19: chr19-8367504; COSMIC: COSV56848443; COSMIC: COSV56848443;