chr4-73484278-A-G

Position:

• chr4-73484278-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001133.2(AFM):​c.158A>G​(p.Gln53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AFM NM_001133.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

Genes affected

AFM (HGNC:316): (afamin) This gene is a member of the albumin gene family, which is comprised of four genes that localize to chromosome 4 in a tandem arrangement. These four genes encode structurally-related serum transport proteins that are known to be evolutionarily related. The protein encoded by this gene is regulated developmentally, expressed in the liver and secreted into the bloodstream. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFM	NM_001133.2	c.158A>G	p.Gln53Arg	missense_variant	3/15	ENST00000226355.5	NP_001124.1
AFM	XM_017007842.3	c.158A>G	p.Gln53Arg	missense_variant	3/13		XP_016863331.1
AFM	XM_017007843.3	c.158A>G	p.Gln53Arg	missense_variant	3/11		XP_016863332.1
AFM	XM_017007844.3	c.158A>G	p.Gln53Arg	missense_variant	3/11		XP_016863333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFM	ENST00000226355.5	c.158A>G	p.Gln53Arg	missense_variant	3/15	1	NM_001133.2	ENSP00000226355.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.158A>G (p.Q53R) alteration is located in exon 3 (coding exon 3) of the AFM gene. This alteration results from a A to G substitution at nucleotide position 158, causing the glutamine (Q) at amino acid position 53 to be replaced by an arginine (R). 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	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.93		Loss of helix (P = 0.2022);
MVP		0.82
MPC		0.019
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.85
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: 11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-74349995;