rs34389944

Variant names:

• chr11-5234357-C-T
• rs34389944
• NM_000519.4:c.77G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000519.4(HBD):​c.77G>A​(p.Gly26Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G26S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: HBD NM_000519.4 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: -0.302
• Publications: 2 publications found

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]

HBD Gene-Disease associations (from GenCC):

• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000519.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBD	NM_000519.4	MANE Select	c.77G>A	p.Gly26Asp	missense	Exon 1 of 3	NP_000510.1	P02042

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBD	ENST00000650601.1	MANE Select	c.77G>A	p.Gly26Asp	missense	Exon 1 of 3	ENSP00000497529.1	P02042
	HBD	ENST00000643122.1		c.77G>A	p.Gly26Asp	missense	Exon 2 of 4	ENSP00000494708.1	P02042
	HBD	ENST00000292901.7	TSL:3	c.77G>A	p.Gly26Asp	missense	Exon 1 of 3	ENSP00000292901.3	E9PFT6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	HEMOGLOBIN A(2) YOKOSHIMA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		-0.30
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.071	T
Polyphen		1.0	D
Vest4		0.74
MutPred		0.83		Loss of methylation at R31 (P = 0.1333)
MVP		0.94
MPC		0.023
ClinPred		0.68	D
GERP RS		-1.3
PromoterAI		-0.054	Neutral
Varity_R		0.93
gMVP		0.85
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs34389944; hg19: chr11-5255587;