Genetic Variant NM_000519.4:c.401T>C (chr11-5233007-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000519.4(HBD):c.401T>C(p.Val134Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

HBD
NM_000519.4 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 4.91

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

delta-beta-thalassemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HBD links:

ENSG00000298932 (HGNC:):

ENSG00000298932 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39180028).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBD	NM_000519.4	MANE Select	c.401T>C	p.Val134Ala	missense	Exon 3 of 3	NP_000510.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HBD	ENST00000650601.1	MANE Select	c.401T>C	p.Val134Ala	missense	Exon 3 of 3	ENSP00000497529.1
HBD	ENST00000643122.1		c.401T>C	p.Val134Ala	missense	Exon 4 of 4	ENSP00000494708.1
HBD	ENST00000417377.1	TSL:3	c.178T>C	p.Trp60Arg	missense	Exon 2 of 2	ENSP00000414741.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111948

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN A(2) NINIVE

Other:1

Dec 12, 2017

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

Eigen

Benign

0.064

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.39

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.6

PhyloP100

4.9

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.64

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.030

Polyphen

0.055

Vest4

0.21

MutPred

0.65

Gain of ubiquitination at K133 (P = 0.1375)

MVP

0.92

MPC

0.013

ClinPred

0.75

GERP RS

3.7

Varity_R

0.39

gMVP

0.60

Mutation Taster

=25/75

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over