11-5234420-G-A

Variant names:

• chr11-5234420-G-A
• rs35406175
• NM_000519.4:c.14C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_000519.4(HBD):​c.14C>T​(p.Thr5Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,612,808 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T5S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: HBD NM_000519.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.73

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_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022682875).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBD	NM_000519.4	c.14C>T	p.Thr5Ile	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.14C>T	p.Thr5Ile	missense_variant	Exon 1 of 3		NM_000519.4	ENSP00000497529.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00143 AC: 360 AN: 251150 Hom.: 1 AF XY: 0.00155 AC XY: 211 AN XY: 135726

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00163 AC: 2377 AN: 1460478 Hom.: 4 Cov.: 30 AF XY: 0.00164 AC XY: 1191 AN XY: 726686

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00204

Gnomad4 NFE exome AF: 0.00185

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74494

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00203

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00121

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00144 AC: 175

EpiCase AF: 0.00196

EpiControl AF: 0.00202

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

delta Thalassemia Uncertain:1

Oct 23, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBD c.14C>T (p.Thr5Ile) missense variant is reported across the literature in 31 individuals with varying thalassemia phenotypes, including in three compound heterozygotes, 18 heterozygotes, six cases where zygosity was not reported, and four individuals who carried multiple HBD variants in cis (Trifillis et al. 1993; De Angioletti et al. 2002; Lacerra et al. 2008; Phylipsen et al. 2011; Liu et al. 2013; Joly et al. 2013; Khalil et al. 2014; Hassan et al. 2014; Villegas et al. 2016). In the majority of these cases, the individuals carried variants in other thalassemia-associated genes so it is unclear which variant may be causative. The p.Thr5Ile variant is reported at a frequency of 0.014019 in the Iberian populations in Spain from the 1000 Genomes Project. Additionally, one homozygote is reported in the European (non-Finnish) population of the Exome Aggregation Consortium and the Genome Aggregation Database. The p.Thr5Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for delta thalassemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;T;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.88	D;.;.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.023	T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	4.0	.;H;H;H;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.1	D;.;D;.;D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;.;D;.;D;D
Sift4G	Uncertain	0.021	D;.;D;.;D;.
Polyphen		0.69	.;P;P;P;.;.
Vest4		0.77
MVP		0.92
MPC		0.021
ClinPred		0.13	T
GERP RS		1.6
Varity_R		0.85
gMVP		0.94

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: rs35406175; hg19: chr11-5255650;