rs2722985

Variant names:

• chr7-83408435-C-A
• rs2722985
• NM_012431.3:c.603G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012431.3(SEMA3E):​c.603G>T​(p.Ala201Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 1,613,168 control chromosomes in the GnomAD database, including 294,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22454 hom., cov: 33)
  • Exomes 𝑓: 0.60 (271969 hom.)
• Consequence: SEMA3E NM_012431.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.85
• Publications: 28 publications found

Genes affected

SEMA3E (HGNC:10727): (semaphorin 3E) Semaphorins are a large family of conserved secreted and membrane associated proteins which possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Based on sequence and structural similarities, semaphorins are put into eight classes: invertebrates contain classes 1 and 2, viruses have class V, and vertebrates contain classes 3-7. Semaphorins serve as axon guidance ligands via multimeric receptor complexes, some (if not all) containing plexin proteins. This gene encodes a class 4 semaphorin. This gene encodes a class 3 semaphorin. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

SEMA3E Gene-Disease associations (from GenCC):

• CHD7-related CHARGE syndrome

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• CHARGE syndrome

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Kallmann syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 7-83408435-C-A is Benign according to our data. Variant chr7-83408435-C-A is described in ClinVar as Benign. ClinVar VariationId is 260255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012431.3. 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
	SEMA3E	NM_012431.3	MANE Select	c.603G>T	p.Ala201Ala	synonymous	Exon 6 of 17	NP_036563.1	O15041-1
	SEMA3E	NM_001178129.2		c.423G>T	p.Ala141Ala	synonymous	Exon 6 of 17	NP_001171600.1	O15041-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA3E	ENST00000643230.2	MANE Select	c.603G>T	p.Ala201Ala	synonymous	Exon 6 of 17	ENSP00000496491.1	O15041-1
	SEMA3E	ENST00000891111.1		c.603G>T	p.Ala201Ala	synonymous	Exon 6 of 17	ENSP00000561170.1
	SEMA3E	ENST00000642232.1		c.603G>T	p.Ala201Ala	synonymous	Exon 6 of 17	ENSP00000494064.1	A0A2R8YCX5

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77125 AN: 151964 Hom.: 22439 Cov.: 33

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.530

GnomAD2 exomes AF: 0.616 AC: 154315 AN: 250570 AF XY: 0.617

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.707

Gnomad ASJ exome AF: 0.438

Gnomad EAS exome AF: 0.879

Gnomad FIN exome AF: 0.669

Gnomad NFE exome AF: 0.600

Gnomad OTH exome AF: 0.601

GnomAD4 exome AF: 0.604 AC: 882062 AN: 1461086 Hom.: 271969 Cov.: 45 AF XY: 0.604 AC XY: 439322 AN XY: 726802

African (AFR) AF: 0.190 AC: 6350 AN: 33460

American (AMR) AF: 0.700 AC: 31234 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 11523 AN: 26130

East Asian (EAS) AF: 0.833 AC: 33041 AN: 39678

South Asian (SAS) AF: 0.653 AC: 56300 AN: 86242

European-Finnish (FIN) AF: 0.668 AC: 35629 AN: 53370

Middle Eastern (MID) AF: 0.484 AC: 2788 AN: 5764

European-Non Finnish (NFE) AF: 0.603 AC: 670076 AN: 1111480

Other (OTH) AF: 0.582 AC: 35121 AN: 60356

GnomAD4 genome AF: 0.507 AC: 77153 AN: 152082 Hom.: 22454 Cov.: 33 AF XY: 0.517 AC XY: 38452 AN XY: 74334

African (AFR) AF: 0.209 AC: 8661 AN: 41506

American (AMR) AF: 0.628 AC: 9573 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1541 AN: 3468

East Asian (EAS) AF: 0.849 AC: 4385 AN: 5166

South Asian (SAS) AF: 0.675 AC: 3258 AN: 4824

European-Finnish (FIN) AF: 0.678 AC: 7166 AN: 10574

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.598 AC: 40681 AN: 67980

Other (OTH) AF: 0.532 AC: 1121 AN: 2108

Alfa AF: 0.559 Hom.: 67726

Bravo AF: 0.493

Asia WGS AF: 0.741 AC: 2577 AN: 3478

EpiCase AF: 0.587

EpiControl AF: 0.582

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	CHARGE syndrome (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.70
DANN	Benign	0.62
PhyloP100		-4.8
Mutation Taster		=85/15	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: rs2722985; hg19: chr7-83037751; COSMIC: COSV57090572;