Genetic Variant SEMA4A:c.*770C>T (chr1-156177767-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022367.4(SEMA4A):c.*770C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 152,758 control chromosomes in the GnomAD database, including 18,040 homozygotes. 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: 𝑓 0.47 ( 17970 hom., cov: 30)

Exomes 𝑓: 0.38 ( 70 hom. )

Consequence

SEMA4A
NM_022367.4 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0420

Publications

13 publications found

Variant links:

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

SEMA4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4A	NM_022367.4 link	c.*770C>T		downstream_gene_variant		ENST00000368285.8	NP_071762.2	Q9H3S1-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
SEMA4A	ENST00000368285.8 link	c.*770C>T	downstream_gene_variant	1	NM_022367.4	ENSP00000357268.3	Q9H3S1-1
SEMA4A	ENST00000355014.6 link	c.*770C>T	downstream_gene_variant	1		ENSP00000347117.2	Q9H3S1-1
SEMA4A	ENST00000368282.1 link	c.*770C>T	downstream_gene_variant	1		ENSP00000357265.1	Q9H3S1-1
SEMA4A	ENST00000368284.5 link	c.*770C>T	downstream_gene_variant	2		ENSP00000357267.1	Q9H3S1-2

Frequencies

GnomAD3 genomes

AF:

0.469

AC:

71188

AN:

151786

Hom.:

17929

Cov.:

show subpopulations

Gnomad AFR

AF:

0.650

Gnomad AMI

AF:

0.372

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.420

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.324

Gnomad FIN

AF:

0.429

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.422

Gnomad OTH

AF:

0.443

GnomAD4 exome

AF:

0.382

AC:

326

AN:

854

Hom.:

Cov.:

AF XY:

0.397

AC XY:

201

AN XY:

506

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AF:

0.167

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.424

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.439

AC:

151

AN:

344

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.346

AC:

121

AN:

350

Other (OTH)

AF:

0.375

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.469

AC:

71277

AN:

151904

Hom.:

17970

Cov.:

AF XY:

0.464

AC XY:

34413

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.650

AC:

26924

AN:

41408

American (AMR)

AF:

0.403

AC:

6155

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.420

AC:

1454

AN:

3466

East Asian (EAS)

AF:

0.121

AC:

627

AN:

5174

South Asian (SAS)

AF:

0.325

AC:

1560

AN:

4804

European-Finnish (FIN)

AF:

0.429

AC:

4521

AN:

10544

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.422

AC:

28669

AN:

67942

Other (OTH)

AF:

0.439

AC:

925

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1818

3636

5454

7272

9090

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

626

1252

1878

2504

3130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.436

Hom.:

40589

Bravo

AF:

0.475

Asia WGS

AF:

0.239

AC:

832

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.65

(source)

DANN

Benign

0.55

PhyloP100

-0.042

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over