15-90217828-A-T

Variant names:

• chr15-90217828-A-T
• rs1001670615
• NM_198925.4:c.383A>T

Variant summary

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

The NM_001324030.3(SEMA4B):​c.-86A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000274 in 1,459,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SEMA4B NM_001324030.3 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.9734
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.81
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324030.3. 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.383A>T	p.Gln128Leu	missense splice_region	Exon 3 of 14	NP_945119.1	Q9NPR2-1
	SEMA4B	NM_001324030.3		c.-86A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	NP_001310959.1
	SEMA4B	NM_001324034.3		c.383A>T	p.Gln128Leu	missense splice_region	Exon 3 of 14	NP_001310963.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4B	ENST00000411539.7	TSL:1 MANE Select	c.383A>T	p.Gln128Leu	missense splice_region	Exon 3 of 14	ENSP00000394720.2	Q9NPR2-1
	SEMA4B	ENST00000332496.10	TSL:1	c.383A>T	p.Gln128Leu	missense splice_region	Exon 4 of 15	ENSP00000332204.6	Q9NPR2-1
	SEMA4B	ENST00000560089.5	TSL:1	n.*219A>T		splice_region non_coding_transcript_exon	Exon 4 of 15	ENSP00000453484.1	H0YM68

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459146 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 725616

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110670

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Benign	0.80
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.2	T
PhyloP100		4.8
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Vest4		0.30
MVP		0.38
MPC		0.51
ClinPred		0.95	D
GERP RS		5.6
gMVP		0.72
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.050		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: rs1001670615; hg19: chr15-90761060;