Genetic Variant NM_001355436.2:c.*858G>A (chr14-64748448-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001355436.2(SPTB):c.*858G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 152,144 control chromosomes in the GnomAD database, including 3,878 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 0.21 ( 3877 hom., cov: 32)

Exomes 𝑓: 0.23 ( 1 hom. )

Consequence

SPTB
NM_001355436.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.33

Publications

9 publications found

Variant links:

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 links:

PLEKHG3 (HGNC:20364): (pleckstrin homology and RhoGEF domain containing G3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHG3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2 link	c.*858G>A		3_prime_UTR_variant	Exon 36 of 36	ENST00000644917.1	NP_001342365.1
PLEKHG3	NM_001308147.2 link	c.*4745C>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000247226.13	NP_001295076.1	A1L390-1A0A2X0SFH4

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPTB	ENST00000644917.1 link	c.*858G>A	3_prime_UTR_variant	Exon 36 of 36		NM_001355436.2	ENSP00000495909.1	P11277-2
PLEKHG3	ENST00000247226.13 link	c.*4745C>T	3_prime_UTR_variant	Exon 17 of 17	1	NM_001308147.2	ENSP00000247226.8	A1L390-1
PLEKHG3	ENST00000634379.2 link	c.*4745C>T	3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000489373.2	A0A0U1RR71
SPTB	ENST00000389722.7 link	c.*858G>A	3_prime_UTR_variant	Exon 35 of 35	2		ENSP00000374372.3	P11277-2

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

31981

AN:

151964

Hom.:

3873

Cov.:

show subpopulations

Gnomad AFR

AF:

0.328

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.0486

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.194

Gnomad MID

AF:

0.0924

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.185

GnomAD4 exome

AF:

0.226

AC:

AN:

Hom.:

Cov.:

AF XY:

0.238

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.185

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.211

AC:

32015

AN:

152082

Hom.:

3877

Cov.:

AF XY:

0.210

AC XY:

15583

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.328

AC:

13598

AN:

41430

American (AMR)

AF:

0.130

AC:

1985

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

454

AN:

3472

East Asian (EAS)

AF:

0.0486

AC:

251

AN:

5168

South Asian (SAS)

AF:

0.187

AC:

899

AN:

4820

European-Finnish (FIN)

AF:

0.194

AC:

2057

AN:

10606

Middle Eastern (MID)

AF:

0.0856

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.180

AC:

12263

AN:

67964

Other (OTH)

AF:

0.184

AC:

389

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1262

2524

3785

5047

6309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

336

672

1008

1344

1680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.181

Hom.:

3159

Bravo

AF:

0.207

Asia WGS

AF:

0.167

AC:

584

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.18

(source)

DANN

Benign

0.59

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over