10-50814012-C-A

Variant names:

• chr10-50814012-C-A
• rs41274050
• NM_014576.4:c.1168G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014576.4(A1CF):​c.1168G>T​(p.Gly390Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G390S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: A1CF NM_014576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.65
• Publications: 13 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014576.4. 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
	A1CF	NM_014576.4	MANE Select	c.1168G>T	p.Gly390Cys	missense	Exon 10 of 13	NP_055391.2
	A1CF	NM_001198819.2		c.1216G>T	p.Gly406Cys	missense	Exon 12 of 15	NP_001185748.1	F8W9F8
	A1CF	NM_001198820.2		c.1192G>T	p.Gly398Cys	missense	Exon 11 of 14	NP_001185749.1	Q9NQ94-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A1CF	ENST00000373997.8	TSL:1 MANE Select	c.1168G>T	p.Gly390Cys	missense	Exon 10 of 13	ENSP00000363109.3	Q9NQ94-2
	A1CF	ENST00000373993.6	TSL:1	c.1192G>T	p.Gly398Cys	missense	Exon 9 of 12	ENSP00000363105.1	Q9NQ94-1
	A1CF	ENST00000855032.1		c.1246G>T	p.Gly416Cys	missense	Exon 12 of 15	ENSP00000525091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250812 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461496 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727080

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111798

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.59		Loss of sheet (P = 0.0054)
MVP		0.36
MPC		0.84
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.47
gMVP		0.96
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41274050; hg19: chr10-52573772;