rs3752382

Positions:

• chr11-5232709-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP7 BS2_Supporting

The ENST00000292901.7(HBD):​c.405C>T​(p.Thr135Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 1,608,686 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (10 hom.)
• Consequence: HBD ENST00000292901.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.879

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-0.879 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.5232709G>A		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000292901.7	c.405C>T	p.Thr135Thr	synonymous_variant	3/3	3		ENSP00000292901.3

Frequencies

GnomAD3 genomes AF: 0.000428 AC: 65 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000615 AC: 145 AN: 235804 Hom.: 1 AF XY: 0.000534 AC XY: 69 AN XY: 129280

Gnomad AFR exome AF: 0.0000714

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00717

Gnomad SAS exome AF: 0.000102

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000502 AC: 731 AN: 1456604 Hom.: 10 Cov.: 32 AF XY: 0.000464 AC XY: 336 AN XY: 724130

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.0160

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000496

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0109

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000499 Hom.: 0

Bravo AF: 0.000249

Asia WGS AF: 0.00491 AC: 17 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.67
DANN	Benign	0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3752382; hg19: chr11-5253939; COSMIC: COSV53083115; COSMIC: COSV53083115;