rs36049174

Positions:

• chr11-5233056-T-C
• chr11-5233056-T-G

Variant summary

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

The NM_000519.4(HBD):​c.352A>G​(p.Asn118Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: HBD NM_000519.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0970

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=0.21232235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBD	NM_000519.4	c.352A>G	p.Asn118Asp	missense_variant	3/3	ENST00000650601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBD	ENST00000650601.1	c.352A>G	p.Asn118Asp	missense_variant	3/3		NM_000519.4	P1
HBD	ENST00000643122.1	c.352A>G	p.Asn118Asp	missense_variant	4/4			P1
HBD	ENST00000417377.1	c.129A>G	p.Ala43=	synonymous_variant	2/2	3
HBD	ENST00000292901.7	c.316-258A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.024	T;T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.37	T
Polyphen		0.0	B;B;B
Vest4		0.69
MutPred		0.69		Loss of ubiquitination at K121 (P = 0.0896);Loss of ubiquitination at K121 (P = 0.0896);Loss of ubiquitination at K121 (P = 0.0896);
MVP		0.90
MPC		0.013
ClinPred		0.15	T
GERP RS		1.8
Varity_R		0.37
gMVP		0.44

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: rs36049174; hg19: chr11-5254286;