5-142314268-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001127496.3(SPRY4):c.841G>A(p.Val281Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000844 in 1,613,460 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0047 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 4 hom. )

Consequence

SPRY4
NM_001127496.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter P:1U:1B:1

Conservation

PhyloP100: 6.93

Publications

8 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
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypogonadotropic hypogonadism 17 with or without anosmia
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

SPRY4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006038159).

BP6

Variant 5-142314268-C-T is Benign according to our data. Variant chr5-142314268-C-T is described in ClinVar as Benign. ClinVar VariationId is 50873.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00467 (711/152334) while in subpopulation AFR AF = 0.0165 (686/41560). AF 95% confidence interval is 0.0155. There are 6 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 711 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRY4	NM_001127496.3 link	c.841G>A	p.Val281Ile	missense_variant	Exon 2 of 2	ENST00000434127.3	NP_001120968.1	Q9C004-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPRY4	ENST00000434127.3 link	c.841G>A	p.Val281Ile	missense_variant	Exon 2 of 2	1	NM_001127496.3	ENSP00000399468.2	Q9C004-1
SPRY4	ENST00000344120.4 link	c.910G>A	p.Val304Ile	missense_variant	Exon 3 of 3	1		ENSP00000344967.4	A0A0C4DFS6
SPRY4	ENST00000643792.1 link	n.1523G>A		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00466

AC:

710

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0165

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.0000294

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00123

AC:

306

AN:

249668

AF XY:

0.000784

show subpopulations

Gnomad AFR exome

AF:

0.0172

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000445

AC:

650

AN:

1461126

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

274

AN XY:

726888

show subpopulations

African (AFR)

AF:

0.0161

AC:

538

AN:

33478

American (AMR)

AF:

0.000738

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52830

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111920

Other (OTH)

AF:

0.00106

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00467

AC:

711

AN:

152334

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

299

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0165

AC:

686

AN:

41560

American (AMR)

AF:

0.00118

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

109

146

182

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:

0.00174

Hom.:

Bravo

AF:

0.00567

ESP6500AA

AF:

0.0195

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00170

AC:

207

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 17 with or without anosmia

Pathogenic:1Uncertain:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

NM_030964.3:c.910G>A in the SPRY4 gene has an allele frequency of 0.017 in African subpopulation in the gnomAD database. This variant has been reported in an individual with normosmic idiopathic hypogonadotropic hypogonadism (PMID: 23643382). The available evidence is currently insufficient to determine the role of this variant in disease. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP4. -

May 02, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0060

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.8

.;L

PhyloP100

6.9

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.67

N;N

REVEL

Benign

0.15

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.14

.;B

Vest4

0.34

MVP

0.75

MPC

0.83

ClinPred

0.024

GERP RS

5.0

Varity_R

0.25

gMVP

0.25

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over