chr15-90223562-G-A

Variant names:

• chr15-90223562-G-A
• rs763754448
• NM_198925.4:c.865G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_198925.4(SEMA4B):​c.865G>A​(p.Asp289Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000419 in 1,433,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: SEMA4B NM_198925.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

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.865G>A	p.Asp289Asn	missense	Exon 8 of 14	NP_945119.1	Q9NPR2-1
	SEMA4B	NM_001324034.3		c.865G>A	p.Asp289Asn	missense	Exon 8 of 14	NP_001310963.1
	SEMA4B	NM_001324031.4		c.865G>A	p.Asp289Asn	missense	Exon 9 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.865G>A	p.Asp289Asn	missense	Exon 8 of 14	ENSP00000394720.2	Q9NPR2-1
	SEMA4B	ENST00000332496.10	TSL:1	c.865G>A	p.Asp289Asn	missense	Exon 9 of 15	ENSP00000332204.6	Q9NPR2-1
	SEMA4B	ENST00000558065.1	TSL:1	n.1066G>A		non_coding_transcript_exon	Exon 5 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228716 AF XY: 0.00000805

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000970

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000419 AC: 6 AN: 1433634 Hom.: 0 Cov.: 33 AF XY: 0.00000423 AC XY: 3 AN XY: 709802

African (AFR) AF: 0.00 AC: 0 AN: 32862

American (AMR) AF: 0.00 AC: 0 AN: 41984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24386

East Asian (EAS) AF: 0.00 AC: 0 AN: 39288

South Asian (SAS) AF: 0.00 AC: 0 AN: 83054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.00000548 AC: 6 AN: 1095416

Other (OTH) AF: 0.00 AC: 0 AN: 59106

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.37	D
PhyloP100		10
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.97
MVP		0.78
MPC		0.84
ClinPred		1.0	D
GERP RS		5.1
gMVP		0.89
Mutation Taster		=42/58	disease causing

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: rs763754448; hg19: chr15-90766794; COSMIC: COSV100203146; COSMIC: COSV100203146;