chr14-64803673-G-A

Position:

• chr14-64803673-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001355436.2(SPTB):​c.408C>T​(p.His136His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.076 in 1,614,004 control chromosomes in the GnomAD database, including 5,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (340 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4945 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.14

Genes affected

SPTB (HGNC:11274): (spectrin beta, erythrocytic) This locus encodes a member of the spectrin gene family. Spectrin proteins, along with ankyrin, play a role in cell membrane organization and stability. The protein encoded by this locus functions in stability of erythrocyte membranes, and mutations in this gene have been associated with spherocytosis type 2, hereditary elliptocytosis, and neonatal hemolytic anemia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-64803673-G-A is Benign according to our data. Variant chr14-64803673-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64803673-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0895 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.408C>T	p.His136His	synonymous_variant	4/36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.408C>T	p.His136His	synonymous_variant	4/36		NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000389722.7	c.408C>T	p.His136His	synonymous_variant	3/35	2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.408C>T	p.His136His	synonymous_variant	4/32	5		ENSP00000374370.4

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 8995 AN: 152028 Hom.: 340 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0531

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0779

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0914

Gnomad OTH AF: 0.0475

GnomAD3 exomes AF: 0.0609 AC: 15316 AN: 251388 Hom.: 616 AF XY: 0.0621 AC XY: 8437 AN XY: 135878

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0364

Gnomad ASJ exome AF: 0.0508

Gnomad EAS exome AF: 0.00484

Gnomad SAS exome AF: 0.0298

Gnomad FIN exome AF: 0.0766

Gnomad NFE exome AF: 0.0906

Gnomad OTH exome AF: 0.0614

GnomAD4 exome AF: 0.0777 AC: 113600 AN: 1461858 Hom.: 4945 Cov.: 32 AF XY: 0.0770 AC XY: 55962 AN XY: 727236

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.0390

Gnomad4 ASJ exome AF: 0.0520

Gnomad4 EAS exome AF: 0.00249

Gnomad4 SAS exome AF: 0.0297

Gnomad4 FIN exome AF: 0.0783

Gnomad4 NFE exome AF: 0.0890

Gnomad4 OTH exome AF: 0.0657

GnomAD4 genome AF: 0.0591 AC: 8992 AN: 152146 Hom.: 340 Cov.: 32 AF XY: 0.0583 AC XY: 4332 AN XY: 74360

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.0530

Gnomad4 ASJ AF: 0.0527

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.0295

Gnomad4 FIN AF: 0.0779

Gnomad4 NFE AF: 0.0914

Gnomad4 OTH AF: 0.0470

Alfa AF: 0.0721 Hom.: 357

Bravo AF: 0.0541

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.0864

EpiControl AF: 0.0848

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Elliptocytosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spherocytosis, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.0
DANN	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11623956; hg19: chr14-65270391;