chr11-5234366-G-T

Variant names:

• chr11-5234366-G-T
• rs35395083
• NM_000519.4:c.68C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000519.4(HBD):​c.68C>A​(p.Ala23Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,674 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: HBD NM_000519.4 missense
• Clinical Significance: other no assertion criteria provided O:2
• Conservation: PhyloP100: 0.797
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050525755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBD	NM_000519.4	c.68C>A	p.Ala23Glu	missense_variant	Exon 1 of 3	ENST00000650601.1	NP_000510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000650601.1	c.68C>A	p.Ala23Glu	missense_variant	Exon 1 of 3		NM_000519.4	ENSP00000497529.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251248 AF XY: 0.00000737

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461562 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727110

African (AFR) AF: 0.000239 AC: 8 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111726

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152112 Hom.: 1 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74296

African (AFR) AF: 0.000314 AC: 13 AN: 41404

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

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

Alfa AF: 0.0000986 Hom.: 1

Bravo AF: 0.0000642

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: other

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN A(2) FLATBUSH Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN FLATBUSH (GEORGIA) Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	0.97
DANN	Benign	0.83
DEOGEN2	Benign	0.00068	T;T;T;T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.14	T;.;.;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.051	T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-1.3	.;N;N;N;.;.
PhyloP100		0.80
PrimateAI	Benign	0.33	T
PROVEAN	Benign	2.1	N;.;N;.;N;N
REVEL	Uncertain	0.50
Sift	Benign	1.0	T;.;T;.;T;T
Sift4G	Benign	1.0	T;.;T;.;T;.
Polyphen		0.0	.;B;B;B;.;.
Vest4		0.13
MVP		0.62
MPC		0.012
ClinPred		0.012	T
GERP RS		0.67
PromoterAI		0.015	Neutral
Varity_R		0.12
gMVP		0.55
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35395083; hg19: chr11-5255596;