5-142314382-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001127496.3(SPRY4):c.727G>C(p.Val243Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V243M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SPRY4
NM_001127496.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0860

Publications

0 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: 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 (MetaRNN=0.059882134).

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.727G>C	p.Val243Leu	missense	Exon 2 of 2	NP_001120968.1	Q9C004-1
SPRY4	NM_030964.5		c.796G>C	p.Val266Leu	missense	Exon 3 of 3	NP_112226.2
SPRY4	NM_001293289.3		c.727G>C	p.Val243Leu	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.727G>C	p.Val243Leu	missense	Exon 2 of 2	ENSP00000399468.2	Q9C004-1
SPRY4	ENST00000344120.4	TSL:1	c.796G>C	p.Val266Leu	missense	Exon 3 of 3	ENSP00000344967.4	A0A0C4DFS6
SPRY4	ENST00000889413.1		c.727G>C	p.Val243Leu	missense	Exon 3 of 3	ENSP00000559472.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461646

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727114

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111908

Other (OTH)

AF:

0.00

AC:

AN:

60390

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.4

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.0094

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.84

M_CAP

Benign

0.0043

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.3

PhyloP100

-0.086

PrimateAI

Benign

0.35

PROVEAN

Benign

1.1

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.061

MutPred

0.45

Loss of helix (P = 0.079)

MVP

0.39

MPC

0.34

ClinPred

0.082

GERP RS

-1.5

Varity_R

0.044

gMVP

0.18

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over