4-73404406-C-A

Variant names:

• chr4-73404406-C-A
• rs141733599
• NM_000477.7:c.79C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000477.7(ALB):​c.79C>A​(p.His27Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H27Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ALB NM_000477.7 missense, splice_region
• Scores: Splicing: ADA: 0.00006668
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.229
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hyperthyroxinemia, familial dysalbuminemic

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000477.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33260322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALB	NM_000477.7	c.79C>A	p.His27Asn	missense_variant, splice_region_variant	Exon 1 of 15	ENST00000295897.9	NP_000468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALB	ENST00000295897.9	c.79C>A	p.His27Asn	missense_variant, splice_region_variant	Exon 1 of 15	1	NM_000477.7	ENSP00000295897.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251448 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456300 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725002

African (AFR) AF: 0.0000600 AC: 2 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107062

Other (OTH) AF: 0.00 AC: 0 AN: 60214

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.068	T;D;.;.;.;.;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.53	T;T;T;T;T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.9	.;M;.;M;.;.;.
PhyloP100		0.23
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.4	D;D;.;.;N;D;N
REVEL	Benign	0.16
Sift	Benign	0.11	T;T;.;.;T;T;D
Sift4G	Uncertain	0.034	D;D;D;D;T;D;T
Polyphen		0.38, 0.0020, 0.97	.;B;.;.;B;.;D
Vest4		0.36, 0.42, 0.41, 0.40, 0.37, 0.47
MutPred		0.29		.;Loss of stability (P = 0.0297);Loss of stability (P = 0.0297);Loss of stability (P = 0.0297);Loss of stability (P = 0.0297);Loss of stability (P = 0.0297);Loss of stability (P = 0.0297);
MVP		0.87
MPC		0.26
ClinPred		0.70	D
GERP RS		0.91
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.38
gMVP		0.15
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.042
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: rs141733599; hg19: chr4-74270123;