chr5-142314648-T-C

Position:

• chr5-142314648-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001127496.3(SPRY4):​c.461A>G​(p.Lys154Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,614,212 control chromosomes in the GnomAD database, including 6 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 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: SPRY4 NM_001127496.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: 7.64

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0137890875).
• BP6: Variant 5-142314648-T-C is Benign according to our data. Variant chr5-142314648-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 50872.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 190 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRY4	NM_001127496.3	c.461A>G	p.Lys154Arg	missense_variant	2/2	ENST00000434127.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRY4	ENST00000434127.3	c.461A>G	p.Lys154Arg	missense_variant	2/2	1	NM_001127496.3	P1
SPRY4	ENST00000344120.4	c.530A>G	p.Lys177Arg	missense_variant	3/3	1
SPRY4	ENST00000643792.1	n.1143A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00160 AC: 401 AN: 251202 Hom.: 0 AF XY: 0.00182 AC XY: 247 AN XY: 135868

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00237 AC: 3471 AN: 1461874 Hom.: 6 Cov.: 32 AF XY: 0.00241 AC XY: 1756 AN XY: 727238

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00284

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74492

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00114

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00160 AC: 194

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2015	- -

Hypogonadotropic hypogonadism 17 with or without anosmia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 02, 2013

- -

SPRY4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.76	N;N
REVEL	Benign	0.20
Sift	Benign	0.21	T;T
Sift4G	Benign	0.52	T;T
Polyphen		1.0	.;D
Vest4		0.51
MVP		0.88
MPC		1.0
ClinPred		0.042	T
GERP RS		4.4
Varity_R		0.21
gMVP		0.27

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: rs78310959; hg19: chr5-141694213;