rs35166721

chr11-5234176-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000519.4(HBD):c.130G>A(p.Glu44Lys) 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. Variant has been reported in ClinVar as other (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E44G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBD NM_000519.4 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: -1.15

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1479648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBD	NM_000519.4	c.130G>A	p.Glu44Lys	missense_variant	2/3	ENST00000650601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBD	ENST00000650601.1	c.130G>A	p.Glu44Lys	missense_variant	2/3		NM_000519.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN A(2) MELBOURNE Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.013	T;T;T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.15	T;.;.;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N;.;N;.;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D;.;D;.;D
Sift4G	Benign	0.37	T;.;T;.;.
Polyphen		0.0	.;B;B;B;.
Vest4		0.28
MutPred		0.34		Gain of methylation at E44 (P = 4e-04);Gain of methylation at E44 (P = 4e-04);Gain of methylation at E44 (P = 4e-04);Gain of methylation at E44 (P = 4e-04);Gain of methylation at E44 (P = 4e-04);
MVP		0.76
MPC		0.012
ClinPred		0.28	T
GERP RS		0.075
Varity_R		0.46
gMVP		0.65

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: rs35166721; hg19: chr11-5255406;