15-90221441-C-A

Variant names:

• chr15-90221441-C-A
• rs1187269596
• NM_198925.4:c.670C>A

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.670C>A​(p.Arg224Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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. R224C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SEMA4B NM_198925.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• 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=0.20142701).

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.670C>A	p.Arg224Ser	missense	Exon 6 of 14	NP_945119.1	Q9NPR2-1
	SEMA4B	NM_001324034.3		c.670C>A	p.Arg224Ser	missense	Exon 6 of 14	NP_001310963.1
	SEMA4B	NM_001324031.4		c.670C>A	p.Arg224Ser	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.670C>A	p.Arg224Ser	missense	Exon 6 of 14	ENSP00000394720.2	Q9NPR2-1
	SEMA4B	ENST00000332496.10	TSL:1	c.670C>A	p.Arg224Ser	missense	Exon 7 of 15	ENSP00000332204.6	Q9NPR2-1
	SEMA4B	ENST00000558065.1	TSL:1	n.871C>A		non_coding_transcript_exon	Exon 3 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436104 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712306

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32650

American (AMR) AF: 0.00 AC: 0 AN: 40278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25616

East Asian (EAS) AF: 0.00 AC: 0 AN: 37958

South Asian (SAS) AF: 0.00 AC: 0 AN: 82656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099912

Other (OTH) AF: 0.00 AC: 0 AN: 59542

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0049	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.10
Sift	Benign	0.26	T
Sift4G	Benign	0.73	T
Vest4		0.29
MVP		0.45
MPC		0.90
ClinPred		0.84	D
GERP RS		5.5
PromoterAI		-0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.75

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: rs1187269596; hg19: chr15-90764673;