NM_000519.4:c.365A>T

Variant names:

• chr11-5233043-T-A
• rs35790721
• NM_000519.4:c.365A>T

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 the same amino acid substitution has been previously reported as Likely benign in 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 rank	MANE	Protein	UniProt
HBD	NM_000519.4	c.365A>T	p.Glu122Val	missense_variant	Exon 3 of 3	ENST00000650601.1	NP_000510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000650601.1	c.365A>T	p.Glu122Val	missense_variant	Exon 3 of 3		NM_000519.4	ENSP00000497529.1
HBD	ENST00000643122.1	c.365A>T	p.Glu122Val	missense_variant	Exon 4 of 4			ENSP00000494708.1
HBD	ENST00000417377.1	c.142A>T	p.Asn48Tyr	missense_variant	Exon 2 of 2	3		ENSP00000414741.1
HBD	ENST00000292901.7	c.316-245A>T		intron_variant	Intron 2 of 2	3		ENSP00000292901.3

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

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

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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
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;