rs41265017

Variant names:

• chr1-156176849-G-A
• rs41265017
• NM_022367.4:c.2138G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022367.4(SEMA4A):​c.2138G>A​(p.Arg713Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 1,614,210 control chromosomes in the GnomAD database, including 1,578 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (132 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1446 hom.)
• Consequence: SEMA4A NM_022367.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:17
• Conservation: PhyloP100: 2.13
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022318065).
• BP6: Variant 1-156176849-G-A is Benign according to our data. Variant chr1-156176849-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 3362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0827 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4A	NM_022367.4	MANE Select	c.2138G>A	p.Arg713Gln	missense	Exon 15 of 15	NP_071762.2
	SEMA4A	NM_001193300.2		c.2138G>A	p.Arg713Gln	missense	Exon 16 of 16	NP_001180229.1
	SEMA4A	NM_001193301.2		c.2138G>A	p.Arg713Gln	missense	Exon 15 of 15	NP_001180230.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4A	ENST00000368285.8	TSL:1 MANE Select	c.2138G>A	p.Arg713Gln	missense	Exon 15 of 15	ENSP00000357268.3
	SEMA4A	ENST00000355014.6	TSL:1	c.2138G>A	p.Arg713Gln	missense	Exon 15 of 15	ENSP00000347117.2
	SEMA4A	ENST00000368282.1	TSL:1	c.2138G>A	p.Arg713Gln	missense	Exon 14 of 14	ENSP00000357265.1

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4955 AN: 152214 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.00743

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0385

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0376

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0447

Gnomad OTH AF: 0.0478

GnomAD2 exomes AF: 0.0374 AC: 9405 AN: 251410 AF XY: 0.0399

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.0309

Gnomad ASJ exome AF: 0.0958

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0296

Gnomad NFE exome AF: 0.0446

Gnomad OTH exome AF: 0.0506

GnomAD4 exome AF: 0.0407 AC: 59460 AN: 1461878 Hom.: 1446 Cov.: 34 AF XY: 0.0417 AC XY: 30353 AN XY: 727242

African (AFR) AF: 0.00747 AC: 250 AN: 33480

American (AMR) AF: 0.0317 AC: 1419 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0972 AC: 2540 AN: 26134

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0426 AC: 3673 AN: 86258

European-Finnish (FIN) AF: 0.0278 AC: 1487 AN: 53416

Middle Eastern (MID) AF: 0.0891 AC: 514 AN: 5768

European-Non Finnish (NFE) AF: 0.0421 AC: 46790 AN: 1112004

Other (OTH) AF: 0.0459 AC: 2775 AN: 60394

GnomAD4 genome AF: 0.0325 AC: 4956 AN: 152332 Hom.: 132 Cov.: 32 AF XY: 0.0325 AC XY: 2422 AN XY: 74498

African (AFR) AF: 0.00743 AC: 309 AN: 41578

American (AMR) AF: 0.0384 AC: 588 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 358 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0381 AC: 184 AN: 4832

European-Finnish (FIN) AF: 0.0291 AC: 309 AN: 10620

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0447 AC: 3043 AN: 68022

Other (OTH) AF: 0.0473 AC: 100 AN: 2116

Alfa AF: 0.0430 Hom.: 555

Bravo AF: 0.0319

TwinsUK AF: 0.0348 AC: 129

ALSPAC AF: 0.0384 AC: 148

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0478 AC: 411

ExAC AF: 0.0354 AC: 4297

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0582

EpiControl AF: 0.0551

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	3	Cone-rod dystrophy 10 (3)
-	1	1	Retinitis pigmentosa 35 (2)
-	-	1	Cone-rod dystrophy 10;C1853214:Retinitis pigmentosa 35 (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.064
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.24
Sift	Benign	0.30	T
Sift4G	Benign	0.39	T
Polyphen		0.23	B
Vest4		0.068
MPC		0.21
ClinPred		0.0064	T
GERP RS		4.2
Varity_R		0.059
gMVP		0.32
Mutation Taster		=94/6	polymorphism (auto)

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: rs41265017; hg19: chr1-156146640; COSMIC: COSV61772569; COSMIC: COSV61772569;