rs36049174

Variant names:

• chr11-5233056-T-C
• rs36049174
• NM_000519.4:c.352A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 1 publications found

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]

HBD Gene-Disease associations (from GenCC):

• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21232235).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000519.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBD	NM_000519.4	MANE Select	c.352A>G	p.Asn118Asp	missense	Exon 3 of 3	NP_000510.1	P02042

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBD	ENST00000650601.1	MANE Select	c.352A>G	p.Asn118Asp	missense	Exon 3 of 3	ENSP00000497529.1	P02042
	HBD	ENST00000643122.1		c.352A>G	p.Asn118Asp	missense	Exon 4 of 4	ENSP00000494708.1	P02042
	HBD	ENST00000417377.1	TSL:3	c.129A>G	p.Ala43Ala	synonymous	Exon 2 of 2	ENSP00000414741.1	C9JRG0

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

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.097
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.30
Sift	Benign	0.033	D
Sift4G	Uncertain	0.027	D
Polyphen		0.0	B
Vest4		0.69
MutPred		0.69		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
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs36049174; hg19: chr11-5254286;