rs2075164

Variant names:

• chr1-156175180-G-A
• rs2075164
• NM_022367.4:c.1529G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156175180-G-A
• chr1-156175180-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_022367.4(SEMA4A):​c.1529G>A​(p.Arg510Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,066 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R510W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0025 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (114 hom.)
• Consequence: SEMA4A NM_022367.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 1.76
• Publications: 12 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):

• 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
• retinitis pigmentosa 35

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy 10

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156175179-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 384117.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008191496).
• BP6: Variant 1-156175180-G-A is Benign according to our data. Variant chr1-156175180-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

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.1529G>A	p.Arg510Gln	missense	Exon 13 of 15	NP_071762.2
	SEMA4A	NM_001193300.2		c.1529G>A	p.Arg510Gln	missense	Exon 14 of 16	NP_001180229.1
	SEMA4A	NM_001193301.2		c.1529G>A	p.Arg510Gln	missense	Exon 13 of 15	NP_001180230.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4A	ENST00000368285.8	TSL:1 MANE Select	c.1529G>A	p.Arg510Gln	missense	Exon 13 of 15	ENSP00000357268.3
	SEMA4A	ENST00000355014.6	TSL:1	c.1529G>A	p.Arg510Gln	missense	Exon 13 of 15	ENSP00000347117.2
	SEMA4A	ENST00000368282.1	TSL:1	c.1529G>A	p.Arg510Gln	missense	Exon 12 of 14	ENSP00000357265.1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 387 AN: 152122 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0609

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00584 AC: 1468 AN: 251342 AF XY: 0.00557

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0687

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00242 AC: 3531 AN: 1461826 Hom.: 114 Cov.: 33 AF XY: 0.00244 AC XY: 1772 AN XY: 727224

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00329 AC: 86 AN: 26132

East Asian (EAS) AF: 0.0700 AC: 2780 AN: 39700

South Asian (SAS) AF: 0.00345 AC: 298 AN: 86256

European-Finnish (FIN) AF: 0.00156 AC: 83 AN: 53368

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000106 AC: 118 AN: 1112004

Other (OTH) AF: 0.00252 AC: 152 AN: 60396

GnomAD4 genome AF: 0.00255 AC: 388 AN: 152240 Hom.: 14 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74424

African (AFR) AF: 0.0000722 AC: 3 AN: 41544

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.0612 AC: 317 AN: 5178

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4824

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68002

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00288 Hom.: 31

Bravo AF: 0.00308

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00572 AC: 695

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cone-rod dystrophy 10 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	1	Retinal dystrophy (2)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 35 (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.8
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.12
Sift	Benign	0.039	D
Sift4G	Benign	0.077	T
Polyphen		0.78	P
Vest4		0.23
MVP		0.20
MPC		0.45
ClinPred		0.043	T
GERP RS		3.7
Varity_R		0.55
gMVP		0.60
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2075164; hg19: chr1-156144971; COSMIC: COSV61772592; COSMIC: COSV61772592;