14-64801382-A-C

Variant names:

• chr14-64801382-A-C
• rs17102119
• NM_001355436.2:c.666T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001355436.2(SPTB):​c.666T>G​(p.Phe222Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F222F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.374
• Publications: 4 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• elliptocytosis 3

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001355436.2. 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
	SPTB	NM_001355436.2	MANE Select	c.666T>G	p.Phe222Leu	missense	Exon 7 of 36	NP_001342365.1	P11277-2
	SPTB	NM_001024858.4		c.666T>G	p.Phe222Leu	missense	Exon 6 of 35	NP_001020029.1	P11277-2
	SPTB	NM_001355437.2		c.666T>G	p.Phe222Leu	missense	Exon 7 of 32	NP_001342366.1	P11277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.666T>G	p.Phe222Leu	missense	Exon 7 of 36	ENSP00000495909.1	P11277-2
	SPTB	ENST00000389722.7	TSL:2	c.666T>G	p.Phe222Leu	missense	Exon 6 of 35	ENSP00000374372.3	P11277-2
	SPTB	ENST00000961380.1		c.666T>G	p.Phe222Leu	missense	Exon 8 of 37	ENSP00000631439.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 70

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.37
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.32
Sift	Benign	0.042	D
Sift4G	Uncertain	0.024	D
Polyphen		0.99	D
Vest4		0.64
MutPred		0.73		Gain of disorder (P = 0.0839)
MVP		0.47
MPC		1.7
ClinPred		0.98	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.60
gMVP		0.63
Mutation Taster		=66/34	polymorphism

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: rs17102119; hg19: chr14-65268100;