Genetic Variant HBD:p.Arg105Ser (chr11-5233991-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000519.4(HBD):c.315G>T(p.Arg105Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as other (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

HBD
NM_000519.4 missense, splice_region

Scores

Splicing: ADA: 0.9533

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 1.38

Publications

2 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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

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.315G>T	p.Arg105Ser	missense splice_region	Exon 2 of 3	NP_000510.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HBD	ENST00000650601.1	MANE Select	c.315G>T	p.Arg105Ser	missense splice_region	Exon 2 of 3	ENSP00000497529.1
HBD	ENST00000643122.1		c.315G>T	p.Arg105Ser	missense splice_region	Exon 3 of 4	ENSP00000494708.1
HBD	ENST00000292901.7	TSL:3	c.315G>T	p.Arg105Ser	missense splice_region	Exon 2 of 3	ENSP00000292901.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000145

Hom.:

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN A(2) CAPRI

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

0.86

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.019

Eigen

Benign

0.12

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

3.3

PhyloP100

1.4

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.20

Vest4

0.70

MutPred

0.75

Loss of methylation at R105 (P = 0.1098)

MVP

0.92

MPC

0.017

ClinPred

0.97

GERP RS

2.5

PromoterAI

-0.067

Neutral

(source)

Varity_R

0.73

gMVP

0.49

Mutation Taster

=5/95

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.66

SpliceAI score (max)

0.060

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over