rs1057519374

Variant names:

• chr7-85012812-G-A
• rs1057519374
• NM_001384900.1:c.1738C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_152754.3(SEMA3D):​c.1738C>T​(p.Pro580Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,610,532 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SEMA3D NM_152754.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.16
• Publications: 2 publications found

Genes affected

SEMA3D (HGNC:10726): (semaphorin 3D) This gene encodes a member of the semaphorin III family of secreted signaling proteins that are involved in axon guidance during neuronal development. The encoded protein contains an N-terminal Sema domain, an immunoglobulin like domain and a C-terminal basic domain. The protein encoded by this gene binds neuropilin and plays an important role in cardiovascular development. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-85012812-G-A is Pathogenic according to our data. Variant chr7-85012812-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 224833.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152754.3. 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
	SEMA3D	NM_001384900.1	MANE Select	c.1738C>T	p.Pro580Ser	missense	Exon 17 of 19	NP_001371829.1
	SEMA3D	NM_001384901.1		c.1738C>T	p.Pro580Ser	missense	Exon 18 of 20	NP_001371830.1
	SEMA3D	NM_001384902.1		c.1738C>T	p.Pro580Ser	missense	Exon 19 of 21	NP_001371831.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA3D	ENST00000284136.11	TSL:5 MANE Select	c.1738C>T	p.Pro580Ser	missense	Exon 17 of 19	ENSP00000284136.6
	SEMA3D	ENST00000484038.1	TSL:1	n.864C>T		non_coding_transcript_exon	Exon 8 of 10
	SEMA3D	ENST00000916323.1		c.1738C>T	p.Pro580Ser	missense	Exon 16 of 18	ENSP00000586382.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151748 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458784 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725776

African (AFR) AF: 0.00 AC: 0 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109882

Other (OTH) AF: 0.00 AC: 0 AN: 60176

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151748 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74088

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.0000659 AC: 1 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67826

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Progressive sensorineural hearing impairment (1)
-	1	-	SEMA3D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.27
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.46		Loss of sheet (P = 0.0315)
MVP		0.80
MPC		0.66
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.45
gMVP		0.66
Mutation Taster		=48/52	disease causing (ClinVar)

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: rs1057519374; hg19: chr7-84642128;