rs142204796

Variant names:

• chr7-83367812-C-A
• rs142204796
• NM_012431.3:c.2102G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_012431.3(SEMA3E):​c.2102G>T​(p.Ser701Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,614,098 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. S701R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (46 hom.)
• Consequence: SEMA3E NM_012431.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.399
• Publications: 13 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004215896).
• BP6: Variant 7-83367812-C-A is Benign according to our data. Variant chr7-83367812-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 628 AD,Unknown gene.

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.2102G>T	p.Ser701Ile	missense	Exon 17 of 17	NP_036563.1	O15041-1
	SEMA3E	NM_001178129.2		c.1922G>T	p.Ser641Ile	missense	Exon 17 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.2102G>T	p.Ser701Ile	missense	Exon 17 of 17	ENSP00000496491.1	O15041-1
	SEMA3E	ENST00000891111.1		c.2096G>T	p.Ser699Ile	missense	Exon 17 of 17	ENSP00000561170.1
	SEMA3E	ENST00000643441.1		n.2087G>T		non_coding_transcript_exon	Exon 17 of 17

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 628 AN: 152128 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00516

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.00537 AC: 1350 AN: 251402 AF XY: 0.00561

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00579

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00565 AC: 8261 AN: 1461852 Hom.: 46 Cov.: 32 AF XY: 0.00565 AC XY: 4106 AN XY: 727230

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00280 AC: 125 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 420 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0102 AC: 876 AN: 86258

European-Finnish (FIN) AF: 0.00163 AC: 87 AN: 53414

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5766

European-Non Finnish (NFE) AF: 0.00564 AC: 6269 AN: 1111990

Other (OTH) AF: 0.00669 AC: 404 AN: 60394

GnomAD4 genome AF: 0.00412 AC: 628 AN: 152246 Hom.: 4 Cov.: 32 AF XY: 0.00412 AC XY: 307 AN XY: 74438

African (AFR) AF: 0.000962 AC: 40 AN: 41568

American (AMR) AF: 0.00373 AC: 57 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4826

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00515 AC: 350 AN: 68012

Other (OTH) AF: 0.00617 AC: 13 AN: 2106

Alfa AF: 0.00521 Hom.: 4

Bravo AF: 0.00420

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00519 AC: 630

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CHARGE syndrome (1)
-	-	1	CHARGE syndrome;C0342384:Hypogonadotropic hypogonadism 7 with or without anosmia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	10
DANN	Benign	0.72
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.40
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.14
Sift	Benign	0.17	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.091
MVP		0.81
MPC		0.20
ClinPred		0.0065	T
GERP RS		2.6
Varity_R		0.062
gMVP		0.51
Mutation Taster		=99/1	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: rs142204796; hg19: chr7-82997128;