NM_001355436.2:c.5799-7C>T

Variant names:

• chr14-64769735-G-A
• rs7142689
• NM_001355436.2:c.5799-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001355436.2(SPTB):​c.5799-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,866 control chromosomes in the GnomAD database, including 12,813 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2852 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9961 hom.)
• Consequence: SPTB NM_001355436.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001448
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.25
• Publications: 7 publications found

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]

SPTB Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• elliptocytosis 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-64769735-G-A is Benign according to our data. Variant chr14-64769735-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.5799-7C>T		splice_region_variant, intron_variant	Intron 27 of 35	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.5799-7C>T		splice_region_variant, intron_variant	Intron 27 of 35		NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000553938.5	c.1794-7C>T		splice_region_variant, intron_variant	Intron 8 of 17	1		ENSP00000451324.1
SPTB	ENST00000389722.7	c.5799-7C>T		splice_region_variant, intron_variant	Intron 26 of 34	2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.5799-7C>T		splice_region_variant, intron_variant	Intron 27 of 31	5		ENSP00000374370.4

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24551 AN: 152042 Hom.: 2835 Cov.: 33

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0992

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.00425

Gnomad SAS AF: 0.0354

Gnomad FIN AF: 0.0789

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.132

GnomAD2 exomes AF: 0.0992 AC: 24938 AN: 251318 AF XY: 0.0938

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.0628

Gnomad ASJ exome AF: 0.0923

Gnomad EAS exome AF: 0.00544

Gnomad FIN exome AF: 0.0826

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.0962

GnomAD4 exome AF: 0.107 AC: 155960 AN: 1461704 Hom.: 9961 Cov.: 33 AF XY: 0.104 AC XY: 75760 AN XY: 727174

African (AFR) AF: 0.339 AC: 11359 AN: 33478

American (AMR) AF: 0.0684 AC: 3057 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0983 AC: 2570 AN: 26132

East Asian (EAS) AF: 0.00285 AC: 113 AN: 39700

South Asian (SAS) AF: 0.0398 AC: 3432 AN: 86256

European-Finnish (FIN) AF: 0.0857 AC: 4571 AN: 53362

Middle Eastern (MID) AF: 0.0785 AC: 453 AN: 5768

European-Non Finnish (NFE) AF: 0.111 AC: 123942 AN: 1111904

Other (OTH) AF: 0.107 AC: 6463 AN: 60386

GnomAD4 genome AF: 0.162 AC: 24602 AN: 152162 Hom.: 2852 Cov.: 33 AF XY: 0.157 AC XY: 11706 AN XY: 74392

African (AFR) AF: 0.328 AC: 13581 AN: 41464

American (AMR) AF: 0.0989 AC: 1514 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 358 AN: 3470

East Asian (EAS) AF: 0.00426 AC: 22 AN: 5170

South Asian (SAS) AF: 0.0350 AC: 169 AN: 4830

European-Finnish (FIN) AF: 0.0789 AC: 836 AN: 10602

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7734 AN: 68000

Other (OTH) AF: 0.131 AC: 278 AN: 2116

Alfa AF: 0.140 Hom.: 913

Bravo AF: 0.170

Asia WGS AF: 0.0510 AC: 179 AN: 3478

EpiCase AF: 0.106

EpiControl AF: 0.106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Elliptocytosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spherocytosis, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.30
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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: rs7142689; hg19: chr14-65236453;