4-73412007-G-C

Variant names:

• chr4-73412007-G-C
• rs75002628
• NM_000477.7:c.725G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000477.7(ALB):​c.725G>C​(p.Arg242Pro) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R242H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALB NM_000477.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.976
• Publications: 24 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_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-73412007-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18225.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 4-73412007-G-C is Pathogenic according to our data. Variant chr4-73412007-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 18238.Status of the report is no_assertion_criteria_provided, 0 stars.

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.725G>C	p.Arg242Pro	missense	Exon 7 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.725G>C	p.Arg242Pro	missense	Exon 7 of 15	ENSP00000295897.4	P02768-1
	ALB	ENST00000415165.6	TSL:1	c.149G>C	p.Arg50Pro	missense	Exon 3 of 11	ENSP00000401820.2	C9JKR2
	ALB	ENST00000876051.1		c.788G>C	p.Arg263Pro	missense	Exon 7 of 15	ENSP00000546110.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hyperthyroxinemia, familial dysalbuminemic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		-0.98
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.92		Loss of MoRF binding (P = 0.0011)
MVP		0.99
MPC		0.94
ClinPred		0.88	D
GERP RS		-1.2
Varity_R		0.91
gMVP		0.87
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75002628; hg19: chr4-74277724;