rs34390965

Variant names:

• chr11-5233991-C-A
• rs34390965
• NM_000519.4:c.315G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-5233991-C-A
• chr11-5233991-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_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

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: 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBD	NM_000519.4	c.315G>T	p.Arg105Ser	missense_variant, splice_region_variant	Exon 2 of 3	ENST00000650601.1	NP_000510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000650601.1	c.315G>T	p.Arg105Ser	missense_variant, splice_region_variant	Exon 2 of 3		NM_000519.4	ENSP00000497529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000145 Hom.: 0

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T;T;T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.67	T;.;.;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.3	.;M;M;M
PhyloP100		1.4
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D;.;D;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0010	D;.;D;.
Polyphen		0.20	.;B;B;B
Vest4		0.70
MutPred		0.75		Loss of methylation at R105 (P = 0.1098);Loss of methylation at R105 (P = 0.1098);Loss of methylation at R105 (P = 0.1098);Loss of methylation at R105 (P = 0.1098);
MVP		0.92
MPC		0.017
ClinPred		0.97	D
GERP RS		2.5
PromoterAI		-0.067	Neutral
Varity_R		0.73
gMVP		0.49
Mutation Taster		=5/95	disease causing

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

Other links and lift over

dbSNP: rs34390965; hg19: chr11-5255221;