chr7-84129031-C-G

Variant names:

• chr7-84129031-C-G
• rs6955597
• NM_006080.3:c.333+92G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006080.3(SEMA3A):​c.333+92G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000118 in 845,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: SEMA3A NM_006080.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.81
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3A	NM_006080.3	c.333+92G>C		intron_variant	Intron 3 of 16	ENST00000265362.9	NP_006071.1
SEMA3A	XM_005250110.4	c.333+92G>C		intron_variant	Intron 6 of 19		XP_005250167.1
SEMA3A	XM_047419751.1	c.333+92G>C		intron_variant	Intron 7 of 20		XP_047275707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3A	ENST00000265362.9	c.333+92G>C		intron_variant	Intron 3 of 16	1	NM_006080.3	ENSP00000265362.3
SEMA3A	ENST00000436949.5	c.333+92G>C		intron_variant	Intron 4 of 17	5		ENSP00000415260.1
SEMA3A	ENST00000420047.1	c.333+92G>C		intron_variant	Intron 4 of 4	4		ENSP00000391900.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000118 AC: 1 AN: 845528 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 443908

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20836

American (AMR) AF: 0.0000245 AC: 1 AN: 40784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21064

East Asian (EAS) AF: 0.00 AC: 0 AN: 36122

South Asian (SAS) AF: 0.00 AC: 0 AN: 69788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4510

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 562342

Other (OTH) AF: 0.00 AC: 0 AN: 39798

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.054
DANN	Benign	0.32
PhyloP100		-5.8

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: rs6955597; hg19: chr7-83758347;