15-90221424-C-T

Variant names:

• chr15-90221424-C-T
• rs752703924
• NM_198925.4:c.653C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198925.4(SEMA4B):​c.653C>T​(p.Ser218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,431,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S218W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SEMA4B NM_198925.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.407
• Publications: 0 publications found

Genes affected

SEMA4B (HGNC:10730): (semaphorin 4B) Predicted to enable chemorepellent activity and semaphorin receptor binding activity. Predicted to be involved in several processes, including generation of neurons; neural crest cell migration; and semaphorin-plexin signaling pathway. Predicted to be located in plasma membrane. Predicted to be active in extracellular space. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18680617).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198925.4. 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
	SEMA4B	NM_198925.4	MANE Select	c.653C>T	p.Ser218Leu	missense	Exon 6 of 14	NP_945119.1	Q9NPR2-1
	SEMA4B	NM_001324034.3		c.653C>T	p.Ser218Leu	missense	Exon 6 of 14	NP_001310963.1
	SEMA4B	NM_001324031.4		c.653C>T	p.Ser218Leu	missense	Exon 7 of 15	NP_001310960.2	Q9NPR2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4B	ENST00000411539.7	TSL:1 MANE Select	c.653C>T	p.Ser218Leu	missense	Exon 6 of 14	ENSP00000394720.2	Q9NPR2-1
	SEMA4B	ENST00000332496.10	TSL:1	c.653C>T	p.Ser218Leu	missense	Exon 7 of 15	ENSP00000332204.6	Q9NPR2-1
	SEMA4B	ENST00000558065.1	TSL:1	n.854C>T		non_coding_transcript_exon	Exon 3 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000297 AC: 6 AN: 202274 AF XY: 0.0000276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000561

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 17 AN: 1431260 Hom.: 0 Cov.: 32 AF XY: 0.0000113 AC XY: 8 AN XY: 709380

African (AFR) AF: 0.0000308 AC: 1 AN: 32486

American (AMR) AF: 0.00 AC: 0 AN: 39604

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25558

East Asian (EAS) AF: 0.00 AC: 0 AN: 37552

South Asian (SAS) AF: 0.00 AC: 0 AN: 81904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000137 AC: 15 AN: 1097656

Other (OTH) AF: 0.00 AC: 0 AN: 59384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000386 Hom.: 0

ExAC AF: 0.0000498 AC: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.097
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.41
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.34
MVP		0.27
MPC		0.38
ClinPred		0.15	T
GERP RS		4.5
PromoterAI		0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.66
Mutation Taster		=92/8	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: rs752703924; hg19: chr15-90764656;