chr10-50810003-A-C

Variant names:

• chr10-50810003-A-C
• rs754576524
• NM_014576.4:c.1500T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014576.4(A1CF):​c.1500T>G​(p.Asp500Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: A1CF NM_014576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.218

Genes affected

A1CF (HGNC:24086): (APOBEC1 complementation factor) Mammalian apolipoprotein B mRNA undergoes site-specific C to U deamination, which is mediated by a multi-component enzyme complex containing a minimal core composed of APOBEC-1 and a complementation factor encoded by this gene. The gene product has three non-identical RNA recognition motifs and belongs to the hnRNP R family of RNA-binding proteins. It has been proposed that this complementation factor functions as an RNA-binding subunit and docks APOBEC-1 to deaminate the upstream cytidine. Studies suggest that the protein may also be involved in other RNA editing or RNA processing events. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

ASAH2B (HGNC:23456): (N-acylsphingosine amidohydrolase 2B) Predicted to enable N-acylsphingosine amidohydrolase activity. Predicted to be involved in ceramide catabolic process; long-chain fatty acid biosynthetic process; and sphingosine biosynthetic process. Predicted to be active in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090528965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A1CF	NM_014576.4	c.1500T>G	p.Asp500Glu	missense_variant	Exon 12 of 13	ENST00000373997.8	NP_055391.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
A1CF	ENST00000373997.8	c.1500T>G	p.Asp500Glu	missense_variant	Exon 12 of 13	1	NM_014576.4	ENSP00000363109.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461706 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727152

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1548T>G (p.D516E) alteration is located in exon 14 (coding exon 10) of the A1CF gene. This alteration results from a T to G substitution at nucleotide position 1548, causing the aspartic acid (D) at amino acid position 516 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	14
DANN	Benign	0.63
DEOGEN2	Benign	0.071	.;.;.;.;T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.84	.;T;D;D;T;.;.
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.091	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	.;.;.;N;N;.;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.18	N;.;.;.;N;N;N
REVEL	Benign	0.096
Sift	Benign	1.0	T;.;.;.;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.016	B;.;B;B;B;B;B
Vest4		0.27
MutPred		0.54		.;.;.;Gain of helix (P = 0.0861);Gain of helix (P = 0.0861);.;Gain of helix (P = 0.0861);
MVP		0.061
MPC		0.22
ClinPred		0.11	T
GERP RS		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.27

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: rs754576524; hg19: chr10-52569763;