NM_000477.7:c.1225C>A

Variant names:

• chr4-73416289-C-A
• rs75946332
• NM_000477.7:c.1225C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000477.7(ALB):​c.1225C>A​(p.Gln409Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ALB NM_000477.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.580
• Publications: 6 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08783853).
• BP6: Variant 4-73416289-C-A is Benign according to our data. Variant chr4-73416289-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2420291.

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.1225C>A	p.Gln409Lys	missense	Exon 10 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.1225C>A	p.Gln409Lys	missense	Exon 10 of 15	ENSP00000295897.4	P02768-1
	ALB	ENST00000415165.6	TSL:1	c.649C>A	p.Gln217Lys	missense	Exon 6 of 11	ENSP00000401820.2	C9JKR2
	ALB	ENST00000876051.1		c.1288C>A	p.Gln430Lys	missense	Exon 10 of 15	ENSP00000546110.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251036 AF XY: 0.0000147

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: 0.00000881

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461346 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 726994

African (AFR) AF: 0.00 AC: 0 AN: 33460

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111696

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.2
DANN	Benign	0.69
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.52	N
PhyloP100		-0.58
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.22
Sift	Benign	0.56	T
Sift4G	Benign	0.81	T
Polyphen		0.0010	B
Vest4		0.090
MutPred		0.42		Gain of ubiquitination at Q409 (P = 0.0185)
MVP		0.57
MPC		0.27
ClinPred		0.015	T
GERP RS		-5.6
Varity_R		0.17
gMVP		0.30
Mutation Taster		=82/18	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

dbSNP: rs75946332; hg19: chr4-74282006;