4-73492027-T-A

Variant summary

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

The NM_001133.2(AFM):c.999T>A(p.Phe333Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AFM NM_001133.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0740

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFM	NM_001133.2	c.999T>A	p.Phe333Leu	missense_variant	8/15	ENST00000226355.5
AFM	XM_017007842.3	c.999T>A	p.Phe333Leu	missense_variant	8/13
AFM	XM_017007843.3	c.999T>A	p.Phe333Leu	missense_variant	8/11
AFM	XM_017007844.3	c.999T>A	p.Phe333Leu	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFM	ENST00000226355.5	c.999T>A	p.Phe333Leu	missense_variant	8/15	1	NM_001133.2	P1

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

Nov 08, 2022

The c.999T>A (p.F333L) alteration is located in exon 8 (coding exon 8) of the AFM gene. This alteration results from a T to A substitution at nucleotide position 999, causing the phenylalanine (F) at amino acid position 333 to be replaced by a leucine (L). 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	Pathogenic	0.90
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.21
Sift	Benign	0.083	T
Sift4G	Benign	0.097	T
Polyphen		0.011	B
Vest4		0.39
MutPred		0.87		Gain of glycosylation at T334 (P = 0.036);
MVP		0.39
MPC		0.014
ClinPred		0.52	D
GERP RS		-0.37
Varity_R		0.39
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-74357744;