11-5233007-A-G

Variant names:

• chr11-5233007-A-G
• rs34802738
• NM_000519.4:c.401T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: HBD NM_000519.4 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 4.91

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39180028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBD	NM_000519.4	c.401T>C	p.Val134Ala	missense_variant	Exon 3 of 3	ENST00000650601.1	NP_000510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000650601.1	c.401T>C	p.Val134Ala	missense_variant	Exon 3 of 3		NM_000519.4	ENSP00000497529.1
HBD	ENST00000643122.1	c.401T>C	p.Val134Ala	missense_variant	Exon 4 of 4			ENSP00000494708.1
HBD	ENST00000417377.1	c.178T>C	p.Trp60Arg	missense_variant	Exon 2 of 2	3		ENSP00000414741.1
HBD	ENST00000292901.7	c.316-209T>C		intron_variant	Intron 2 of 2	3		ENSP00000292901.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461804 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T;T;T
Eigen	Benign	0.064
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.70	.;.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.6	M;M;M
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	.;N;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	.;D;.
Sift4G	Uncertain	0.030	.;D;.
Polyphen		0.055	B;B;B
Vest4		0.21
MutPred		0.65		Gain of ubiquitination at K133 (P = 0.1375);Gain of ubiquitination at K133 (P = 0.1375);Gain of ubiquitination at K133 (P = 0.1375);
MVP		0.92
MPC		0.013
ClinPred		0.75	D
GERP RS		3.7
Varity_R		0.39
gMVP		0.60

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: rs34802738; hg19: chr11-5254237;