NM_006080.3:c.453+24A>G

Variant names:

• chr7-84110446-T-C
• rs1990044
• NM_006080.3:c.453+24A>G

Variant summary

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

The NM_006080.3(SEMA3A):​c.453+24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,610,834 control chromosomes in the GnomAD database, including 251,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19315 hom., cov: 32)
  • Exomes 𝑓: 0.56 (232566 hom.)
• Consequence: SEMA3A NM_006080.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.172
• Publications: 14 publications found

Genes affected

SEMA3A (HGNC:10723): (semaphorin 3A) This gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development. Increased expression of this protein is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer's disease. [provided by RefSeq, Jul 2008]

SEMA3A Gene-Disease associations (from GenCC):

• skeletal dysplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hypogonadotropic hypogonadism 16 with or without anosmia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-84110446-T-C is Benign according to our data. Variant chr7-84110446-T-C is described in ClinVar as Benign. ClinVar VariationId is 1293457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3A	NM_006080.3	c.453+24A>G		intron_variant	Intron 4 of 16	ENST00000265362.9	NP_006071.1
SEMA3A	XM_005250110.4	c.453+24A>G		intron_variant	Intron 7 of 19		XP_005250167.1
SEMA3A	XM_047419751.1	c.453+24A>G		intron_variant	Intron 8 of 20		XP_047275707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3A	ENST00000265362.9	c.453+24A>G		intron_variant	Intron 4 of 16	1	NM_006080.3	ENSP00000265362.3
SEMA3A	ENST00000436949.5	c.453+24A>G		intron_variant	Intron 5 of 17	5		ENSP00000415260.1
SEMA3A	ENST00000420047.1	c.*30A>G		downstream_gene_variant		4		ENSP00000391900.1

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74199 AN: 151892 Hom.: 19312 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.530

GnomAD2 exomes AF: 0.539 AC: 134161 AN: 249026 AF XY: 0.536

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.568

Gnomad ASJ exome AF: 0.579

Gnomad EAS exome AF: 0.712

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.563

Gnomad OTH exome AF: 0.554

GnomAD4 exome AF: 0.560 AC: 817631 AN: 1458824 Hom.: 232566 Cov.: 34 AF XY: 0.558 AC XY: 405239 AN XY: 725668

African (AFR) AF: 0.280 AC: 9325 AN: 33312

American (AMR) AF: 0.568 AC: 25238 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 14884 AN: 26008

East Asian (EAS) AF: 0.732 AC: 29029 AN: 39640

South Asian (SAS) AF: 0.439 AC: 37731 AN: 85872

European-Finnish (FIN) AF: 0.527 AC: 28121 AN: 53340

Middle Eastern (MID) AF: 0.501 AC: 2879 AN: 5742

European-Non Finnish (NFE) AF: 0.574 AC: 636938 AN: 1110264

Other (OTH) AF: 0.556 AC: 33486 AN: 60234

GnomAD4 genome AF: 0.488 AC: 74218 AN: 152010 Hom.: 19315 Cov.: 32 AF XY: 0.489 AC XY: 36294 AN XY: 74278

African (AFR) AF: 0.290 AC: 12031 AN: 41476

American (AMR) AF: 0.563 AC: 8577 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1944 AN: 3472

East Asian (EAS) AF: 0.706 AC: 3642 AN: 5162

South Asian (SAS) AF: 0.438 AC: 2106 AN: 4812

European-Finnish (FIN) AF: 0.533 AC: 5634 AN: 10566

Middle Eastern (MID) AF: 0.558 AC: 163 AN: 292

European-Non Finnish (NFE) AF: 0.567 AC: 38512 AN: 67956

Other (OTH) AF: 0.526 AC: 1112 AN: 2114

Alfa AF: 0.525 Hom.: 4598

Bravo AF: 0.487

Asia WGS AF: 0.537 AC: 1862 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.3
DANN	Benign	0.45
PhyloP100		-0.17
Mutation Taster		=100/0	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: rs1990044; hg19: chr7-83739762; COSMIC: COSV54894079; COSMIC: COSV54894079;