rs35406175

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.73

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
HBD	NM_000519.4 linkuse as main transcript	c.14C>T	p.Thr5Ile	missense_variant	1/3	ENST00000650601.1	NP_000510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000650601.1 linkuse as main transcript	c.14C>T	p.Thr5Ile	missense_variant	1/3		NM_000519.4	ENSP00000497529	P1

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

211

AN:

152212

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00155

AC XY:

211

AN XY:

135726

show subpopulations

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.:

Cov.:

AF XY:

0.00164

AC XY:

1191

AN XY:

726686

show subpopulations

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.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74494

show subpopulations

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.:

Bravo

AF:

0.00121

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00233

AC:

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

LINK: link

Submissions by phenotype

delta Thalassemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 23, 2017

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

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

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

LIST_S2

Uncertain

0.88

D;.;.;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.023

T;T;T;T;T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

4.0

.;H;H;H;.;.

MutationTaster

Benign

0.73

N;N

PrimateAI

Uncertain

0.52

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over