rs63750461

Positions:

• chr11-5232986-G-A
• chr11-5232986-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000519.4(HBD):​c.422C>T​(p.Ala141Val) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBD NM_000519.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37

Genes affected

HBD (HGNC:4829): (hemoglobin subunit delta) The delta (HBD) and beta (HBB) genes are normally expressed in the adult: two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin. Two alpha chains plus two delta chains constitute HbA-2, which with HbF comprises the remaining 3% of adult hemoglobin. Five beta-like globin genes are found within a 45 kb cluster on chromosome 11 in the following order: 5'-epsilon--Ggamma--Agamma--delta--beta-3'. Mutations in the delta-globin gene are associated with beta-thalassemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBD	NM_000519.4	c.422C>T	p.Ala141Val	missense_variant	3/3	ENST00000650601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBD	ENST00000650601.1	c.422C>T	p.Ala141Val	missense_variant	3/3		NM_000519.4	P1
HBD	ENST00000643122.1	c.422C>T	p.Ala141Val	missense_variant	4/4			P1
HBD	ENST00000417377.1	c.199C>T	p.Pro67Ser	missense_variant	2/2	3
HBD	ENST00000292901.7	c.316-188C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;T;T
Eigen	Benign	0.0054
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.93	.;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.099	D
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	.;D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.022	.;D;.
Sift4G	Benign	0.12	.;T;.
Polyphen		1.0	D;D;D
Vest4		0.71
MutPred		0.88		Loss of ubiquitination at K145 (P = 0.0699);Loss of ubiquitination at K145 (P = 0.0699);Loss of ubiquitination at K145 (P = 0.0699);
MVP		0.99
MPC		0.087
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.40
gMVP		0.51

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: rs63750461; hg19: chr11-5254216;