chr4-73406760-T-C

Variant names:

• chr4-73406760-T-C
• rs77892378
• NM_000477.7:c.269T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000477.7(ALB):​c.269T>C​(p.Leu90Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALB NM_000477.7 missense, splice_region
• Scores: Splicing: ADA: 0.9073
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.01
• Publications: 10 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 4-73406760-T-C is Pathogenic according to our data. Variant chr4-73406760-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 18239.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.269T>C	p.Leu90Pro	missense splice_region	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.269T>C	p.Leu90Pro	missense splice_region	Exon 3 of 15	ENSP00000295897.4	P02768-1
	ALB	ENST00000415165.6	TSL:1	c.137+1587T>C		intron	N/A	ENSP00000401820.2	C9JKR2
	ALB	ENST00000876051.1		c.332T>C	p.Leu111Pro	missense splice_region	Exon 3 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	0.69
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.67
Sift	Benign	0.061	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.95	P
Vest4		0.87
MutPred		0.87		Loss of stability (P = 0.0164)
MVP		0.97
MPC		1.0
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.76
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Pathogenic	0.74
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: rs77892378; hg19: chr4-74272477;