chr4-73483951-T-G

Position:

• chr4-73483951-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001133.2(AFM):​c.99T>G​(p.Asn33Lys) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AFM NM_001133.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.27

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.

• PM1: In a glycosylation_site N-linked (GlcNAc...) (complex) asparagine (size 0) in uniprot entity AFAM_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12506893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFM	NM_001133.2	c.99T>G	p.Asn33Lys	missense_variant	2/15	ENST00000226355.5	NP_001124.1
AFM	XM_017007842.3	c.99T>G	p.Asn33Lys	missense_variant	2/13		XP_016863331.1
AFM	XM_017007843.3	c.99T>G	p.Asn33Lys	missense_variant	2/11		XP_016863332.1
AFM	XM_017007844.3	c.99T>G	p.Asn33Lys	missense_variant	2/11		XP_016863333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFM	ENST00000226355.5	c.99T>G	p.Asn33Lys	missense_variant	2/15	1	NM_001133.2	ENSP00000226355.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

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

Oct 02, 2023

The c.99T>G (p.N33K) alteration is located in exon 2 (coding exon 2) of the AFM gene. This alteration results from a T to G substitution at nucleotide position 99, causing the asparagine (N) at amino acid position 33 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.034
DANN	Benign	0.87
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.24
Sift	Benign	0.038	D
Sift4G	Benign	0.56	T
Polyphen		0.0050	B
Vest4		0.23
MutPred		0.52		Gain of methylation at N33 (P = 0.0149);
MVP		0.37
MPC		0.012
ClinPred		0.12	T
GERP RS		-9.6
Varity_R		0.11
gMVP		0.083

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: chr4-74349668;