11-5226673-A-T

Position:

• chr11-5226673-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The ENST00000335295.4(HBB):​c.219T>A​(p.Ser73Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB ENST00000335295.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.318

Genes affected

HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in ENST00000335295.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.219T>A	p.Ser73Arg	missense_variant	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.219T>A	p.Ser73Arg	missense_variant	2/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T;T;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.5	M;M;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N;.;.;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0090	D;.;.;D
Sift4G	Benign	0.12	T;.;.;.
Polyphen		0.11	B;B;.;.
Vest4		0.86
MutPred		0.47		Gain of methylation at S73 (P = 0.0199);Gain of methylation at S73 (P = 0.0199);Gain of methylation at S73 (P = 0.0199);Gain of methylation at S73 (P = 0.0199);
MVP		0.82
MPC		0.17
ClinPred		0.48	T
GERP RS		-0.12
Varity_R		0.51
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs34860414; hg19: chr11-5247903;