rs139512218

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001127496.3(SPRY4):c.653C>A(p.Ser218Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00625 in 1,614,168 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 34 hom. )

Consequence

SPRY4
NM_001127496.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3O:1

Conservation

PhyloP100: 9.60

Publications

19 publications found

Variant links:

Genes affected

SPRY4 (HGNC:15533): (sprouty RTK signaling antagonist 4) This gene encodes a member of a family of cysteine- and proline-rich proteins. The encoded protein is an inhibitor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. Activity of this protein impairs the formation of active GTP-RAS. Nucleotide variation in this gene has been associated with hypogonadotropic hypogonadism 17 with or without anosmia. Alternative splicing results in a multiple transcript variants. [provided by RefSeq, Jun 2014]

SPRY4 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 17 with or without anosmia
Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPRY4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013144106).

BP6

Variant 5-142314456-G-T is Benign according to our data. Variant chr5-142314456-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 50874.

BS2

High AC in GnomAd4 at 653 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127496.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPRY4	NM_001127496.3	MANE Select	c.653C>A	p.Ser218Tyr	missense	Exon 2 of 2	NP_001120968.1	Q9C004-1
SPRY4	NM_030964.5		c.722C>A	p.Ser241Tyr	missense	Exon 3 of 3	NP_112226.2
SPRY4	NM_001293289.3		c.653C>A	p.Ser218Tyr	missense	Exon 3 of 3	NP_001280218.1	Q9C004-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPRY4	ENST00000434127.3	TSL:1 MANE Select	c.653C>A	p.Ser218Tyr	missense	Exon 2 of 2	ENSP00000399468.2	Q9C004-1
SPRY4	ENST00000344120.4	TSL:1	c.722C>A	p.Ser241Tyr	missense	Exon 3 of 3	ENSP00000344967.4	A0A0C4DFS6
SPRY4	ENST00000889413.1		c.653C>A	p.Ser218Tyr	missense	Exon 3 of 3	ENSP00000559472.1

Frequencies

GnomAD3 genomes

AF:

0.00429

AC:

653

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00641

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00683

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00446

AC:

1119

AN:

250986

AF XY:

0.00431

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00644

Gnomad NFE exome

AF:

0.00611

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00645

AC:

9436

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00628

AC XY:

4568

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33480

American (AMR)

AF:

0.00405

AC:

181

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00298

AC:

257

AN:

86252

European-Finnish (FIN)

AF:

0.00644

AC:

344

AN:

53416

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00753

AC:

8373

AN:

1111992

Other (OTH)

AF:

0.00394

AC:

238

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

626

1252

1879

2505

3131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

310

620

930

1240

1550

<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:

0.00429

AC:

653

AN:

152306

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41568

American (AMR)

AF:

0.00359

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00332

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00641

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00683

AC:

465

AN:

68036

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00588

Hom.:

Bravo

AF:

0.00393

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00457

AC:

555

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00545

EpiControl

AF:

0.00640

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Amenorrhea (1)

not specified (1)

Hypogonadotropic hypogonadism 17 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.5

PhyloP100

9.6

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.36

MVP

0.92

MPC

1.3

ClinPred

0.023

GERP RS

5.5

Varity_R

0.81

gMVP

0.49

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over