chr11-5234385-C-T

Variant names:

• chr11-5234385-C-T
• rs34012192
• NM_000519.4:c.49G>A

Variant summary

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

The NM_000519.4(HBD):​c.49G>A​(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBD NM_000519.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18

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=0.26962298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBD	NM_000519.4	c.49G>A	p.Gly17Ser	missense_variant	Exon 1 of 3	ENST00000650601.1	NP_000510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000650601.1	c.49G>A	p.Gly17Ser	missense_variant	Exon 1 of 3		NM_000519.4	ENSP00000497529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	0.41
DANN	Benign	0.64
DEOGEN2	Benign	0.014	T;T;T;T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.78	T;.;.;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.84	.;L;L;L;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N;.;N;.;D;N
REVEL	Uncertain	0.49
Sift	Benign	0.061	T;.;T;.;D;T
Sift4G	Benign	0.60	T;.;T;.;T;.
Polyphen		0.0010	.;B;B;B;.;.
Vest4		0.19
MutPred		0.69		Gain of ubiquitination at K18 (P = 0.0822);Gain of ubiquitination at K18 (P = 0.0822);Gain of ubiquitination at K18 (P = 0.0822);Gain of ubiquitination at K18 (P = 0.0822);Gain of ubiquitination at K18 (P = 0.0822);Gain of ubiquitination at K18 (P = 0.0822);
MVP		0.54
MPC		0.012
ClinPred		0.078	T
GERP RS		-9.2
Varity_R		0.20
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs34012192; hg19: chr11-5255615; COSMIC: COSV53083606; COSMIC: COSV53083606;