11-5225611-T-A

Position:

• chr11-5225611-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000518.5(HBB):​c.431A>T​(p.His144Leu) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H144?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.519

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225611-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.431A>T	p.His144Leu	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.431A>T	p.His144Leu	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.431A>T	p.His144Leu	missense_variant	3/3			P1
HBB	ENST00000633227.1	c.*247A>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	3
HBB	ENST00000475226.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.093
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	.;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.12	T;.
Polyphen		0.0090	B;B
Vest4		0.61
MutPred		0.56		Loss of disorder (P = 0.0375);Loss of disorder (P = 0.0375);
MVP		0.93
MPC		0.047
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.81
gMVP		0.83

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: rs33918338; hg19: chr11-5246841;