NM_000477.7:c.199G>A

Variant names:

• chr4-73406690-G-A
• NM_000477.7:c.199G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000477.7(ALB):​c.199G>A​(p.Val67Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALB NM_000477.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19
• Publications: 0 publications found

Genes affected

ALB (HGNC:399): (albumin) This gene encodes the most abundant protein in human blood. This protein functions in the regulation of blood plasma colloid osmotic pressure and acts as a carrier protein for a wide range of endogenous molecules including hormones, fatty acids, and metabolites, as well as exogenous drugs. Additionally, this protein exhibits an esterase-like activity with broad substrate specificity. The encoded preproprotein is proteolytically processed to generate the mature protein. A peptide derived from this protein, EPI-X4, is an endogenous inhibitor of the CXCR4 chemokine receptor. [provided by RefSeq, Jul 2016]

ALB Gene-Disease associations (from GenCC):

• congenital analbuminemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• hyperthyroxinemia, familial dysalbuminemic

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000477.7. 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
	ALB	NM_000477.7	MANE Select	c.199G>A	p.Val67Met	missense	Exon 3 of 15	NP_000468.1	P02768-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALB	ENST00000295897.9	TSL:1 MANE Select	c.199G>A	p.Val67Met	missense	Exon 3 of 15	ENSP00000295897.4	P02768-1
	ALB	ENST00000415165.6	TSL:1	c.137+1517G>A		intron	N/A	ENSP00000401820.2	C9JKR2
	ALB	ENST00000503124.5	TSL:5	c.-40G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	ENSP00000421027.1	D6RHD5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461568 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727100

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111910

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.43
Sift	Benign	0.043	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.92	P
Vest4		0.37
MutPred		0.70		Gain of ubiquitination at K65 (P = 0.0931)
MVP		0.77
MPC		0.64
ClinPred		0.96	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.60
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

hg19: chr4-74272407;