rs369653609

Variant names:

• chr1-156154661-C-A
• rs369653609
• NM_022367.4:c.83C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156154661-C-A
• chr1-156154661-C-T

Variant summary

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

The NM_022367.4(SEMA4A):​c.83C>A​(p.Thr28Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. T28M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SEMA4A NM_022367.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.303
• Publications: 0 publications found

Genes affected

SEMA4A (HGNC:10729): (semaphorin 4A) This gene encodes a member of the semaphorin family of soluble and transmembrane proteins. Semaphorins are involved in numerous functions, including axon guidance, morphogenesis, carcinogenesis, and immunomodulation. The encoded protein is a single-pass type I membrane protein containing an immunoglobulin-like C2-type domain, a PSI domain and a sema domain. It inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons. It is an activator of T-cell-mediated immunity and suppresses vascular endothelial growth factor (VEGF)-mediated endothelial cell migration and proliferation in vitro and angiogenesis in vivo. Mutations in this gene are associated with retinal degenerative diseases including retinitis pigmentosa type 35 (RP35) and cone-rod dystrophy type 10 (CORD10). Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]

SEMA4A Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial colorectal cancer type X

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cone-rod dystrophy 10

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 35

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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=0.08116105).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022367.4. 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
	SEMA4A	NM_022367.4	MANE Select	c.83C>A	p.Thr28Lys	missense	Exon 2 of 15	NP_071762.2
	SEMA4A	NM_001193300.2		c.83C>A	p.Thr28Lys	missense	Exon 3 of 16	NP_001180229.1	Q9H3S1-1
	SEMA4A	NM_001193301.2		c.83C>A	p.Thr28Lys	missense	Exon 2 of 15	NP_001180230.1	Q9H3S1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4A	ENST00000368285.8	TSL:1 MANE Select	c.83C>A	p.Thr28Lys	missense	Exon 2 of 15	ENSP00000357268.3	Q9H3S1-1
	SEMA4A	ENST00000355014.6	TSL:1	c.83C>A	p.Thr28Lys	missense	Exon 2 of 15	ENSP00000347117.2	Q9H3S1-1
	SEMA4A	ENST00000368282.1	TSL:1	c.83C>A	p.Thr28Lys	missense	Exon 1 of 14	ENSP00000357265.1	Q9H3S1-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 227818 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452036 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721308

African (AFR) AF: 0.0000299 AC: 1 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 42816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.00 AC: 0 AN: 84378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108038

Other (OTH) AF: 0.00 AC: 0 AN: 60074

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.0
DANN	Benign	0.87
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.30
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.15
Sift	Benign	0.24	T
Sift4G	Benign	0.15	T
Polyphen		0.011	B
Vest4		0.35
MutPred		0.42		Gain of ubiquitination at T28 (P = 0.0177)
MVP		0.51
MPC		0.20
ClinPred		0.10	T
GERP RS		-1.6
PromoterAI		-0.025	Neutral
Varity_R		0.058
gMVP		0.46
Mutation Taster		=97/3	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: rs369653609; hg19: chr1-156124452;