5-142314268-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Benign criteria provided, single submitter P:1 U:1 B:1
• Conservation: PhyloP100: 6.93

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 710 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRY4	NM_001127496.3	c.841G>A	p.Val281Ile	missense_variant	2/2	ENST00000434127.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRY4	ENST00000434127.3	c.841G>A	p.Val281Ile	missense_variant	2/2	1	NM_001127496.3	P1
SPRY4	ENST00000344120.4	c.910G>A	p.Val304Ile	missense_variant	3/3	1
SPRY4	ENST00000643792.1	n.1523G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 710 AN: 152216 Hom.: 6 Cov.: 32

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

GnomAD3 exomes AF: 0.00123 AC: 306 AN: 249668 Hom.: 3 AF XY: 0.000784 AC XY: 106 AN XY: 135204

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 SAS exome AF: 0.0000654

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.: 4 Cov.: 32 AF XY: 0.000377 AC XY: 274 AN XY: 726888

Gnomad4 AFR exome AF: 0.0161

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152334 Hom.: 6 Cov.: 32 AF XY: 0.00401 AC XY: 299 AN XY: 74476

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000747 Hom.: 2

Bravo AF: 0.00567

ESP6500AA AF: 0.0195 AC: 86

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00170 AC: 207

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

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

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 17 with or without anosmia Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 02, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.64	T
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	T
GERP RS		5.0
Varity_R		0.25
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs142439525; hg19: chr5-141693833;