11-5233043-T-A

Position:

• chr11-5233043-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000519.4(HBD):​c.365A>T​(p.Glu122Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as other (no stars). 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: other no assertion criteria provided O:1
• Conservation: PhyloP100: 1.65

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBD	NM_000519.4	c.365A>T	p.Glu122Val	missense_variant	3/3	ENST00000650601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBD	ENST00000650601.1	c.365A>T	p.Glu122Val	missense_variant	3/3		NM_000519.4	P1
HBD	ENST00000643122.1	c.365A>T	p.Glu122Val	missense_variant	4/4			P1
HBD	ENST00000417377.1	c.142A>T	p.Asn48Tyr	missense_variant	2/2	3
HBD	ENST00000292901.7	c.316-245A>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN A(2) MANZANARES Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.095	T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.97	.;.;D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Pathogenic	3.6	H;H;H
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.0	.;D;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	.;D;.
Sift4G	Benign	0.10	.;T;.
Polyphen		0.50	P;P;P
Vest4		0.41
MutPred		0.45		Loss of disorder (P = 0.0353);Loss of disorder (P = 0.0353);Loss of disorder (P = 0.0353);
MVP		0.93
MPC		0.014
ClinPred		0.97	D
GERP RS		3.6
Varity_R		0.59
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35790721; hg19: chr11-5254273;