11-5234026-A-T

Position:

• chr11-5234026-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000519.4(HBD):​c.280T>A​(p.Cys94Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. C94G) 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: 4.62

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBD	NM_000519.4	c.280T>A	p.Cys94Ser	missense_variant	2/3	ENST00000650601.1	NP_000510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000650601.1	c.280T>A	p.Cys94Ser	missense_variant	2/3		NM_000519.4	ENSP00000497529	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;T;T;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;.;.;T;T
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.4	.;L;L;L;.
MutationTaster	Benign	0.86	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-8.4	D;.;D;.;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;.;D;.;D
Sift4G	Benign	0.62	T;.;T;.;.
Polyphen		0.95	.;P;P;P;.
Vest4		0.23
MutPred		0.74		Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);
MVP		0.96
MPC		0.057
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.92
gMVP		0.64

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: rs28933077; hg19: chr11-5255256;