15-90221424-C-G

Variant names:

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

Variant summary

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

The NM_198925.4(SEMA4B):​c.653C>G​(p.Ser218Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,431,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SEMA4B NM_198925.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>G	p.Ser218Trp	missense	Exon 6 of 14	NP_945119.1	Q9NPR2-1
	SEMA4B	NM_001324034.3		c.653C>G	p.Ser218Trp	missense	Exon 6 of 14	NP_001310963.1
	SEMA4B	NM_001324031.4		c.653C>G	p.Ser218Trp	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>G	p.Ser218Trp	missense	Exon 6 of 14	ENSP00000394720.2	Q9NPR2-1
	SEMA4B	ENST00000332496.10	TSL:1	c.653C>G	p.Ser218Trp	missense	Exon 7 of 15	ENSP00000332204.6	Q9NPR2-1
	SEMA4B	ENST00000558065.1	TSL:1	n.854C>G		non_coding_transcript_exon	Exon 3 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1431262 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 709380

African (AFR) AF: 0.0000616 AC: 2 AN: 32486

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25560

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: 0.00 AC: 0 AN: 1097656

Other (OTH) AF: 0.0000168 AC: 1 AN: 59384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.1	T
PhyloP100		0.41
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.20
Sift	Benign	0.050	D
Sift4G	Benign	0.19	T
Vest4		0.64
MVP		0.32
MPC		0.98
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		0.12	Neutral
gMVP		0.75
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; COSMIC: COSV99061331; COSMIC: COSV99061331;