5-142314111-C-G

Variant names:

• chr5-142314111-C-G
• rs112369222
• NM_001127496.3:c.*98G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127496.3(SPRY4):​c.*98G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,337,840 control chromosomes in the GnomAD database, including 250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (132 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (118 hom.)
• Consequence: SPRY4 NM_001127496.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.462
• Publications: 2 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-142314111-C-G is Benign according to our data. Variant chr5-142314111-C-G is described in ClinVar as Benign. ClinVar VariationId is 1227299.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRY4	NM_001127496.3	MANE Select	c.*98G>C		3_prime_UTR	Exon 2 of 2	NP_001120968.1	Q9C004-1
	SPRY4	NM_030964.5		c.*98G>C		3_prime_UTR	Exon 3 of 3	NP_112226.2
	SPRY4	NM_001293289.3		c.*98G>C		3_prime_UTR	Exon 3 of 3	NP_001280218.1	Q9C004-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRY4	ENST00000434127.3	TSL:1 MANE Select	c.*98G>C		3_prime_UTR	Exon 2 of 2	ENSP00000399468.2	Q9C004-1
	SPRY4	ENST00000344120.4	TSL:1	c.*98G>C		3_prime_UTR	Exon 3 of 3	ENSP00000344967.4	A0A0C4DFS6
	SPRY4	ENST00000889413.1		c.*98G>C		3_prime_UTR	Exon 3 of 3	ENSP00000559472.1

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3549 AN: 152164 Hom.: 131 Cov.: 32

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00261 AC: 3095 AN: 1185558 Hom.: 118 Cov.: 18 AF XY: 0.00226 AC XY: 1318 AN XY: 582386

African (AFR) AF: 0.0844 AC: 2294 AN: 27170

American (AMR) AF: 0.00674 AC: 180 AN: 26720

Ashkenazi Jewish (ASJ) AF: 0.000989 AC: 19 AN: 19204

East Asian (EAS) AF: 0.00 AC: 0 AN: 34864

South Asian (SAS) AF: 0.000458 AC: 30 AN: 65440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31738

Middle Eastern (MID) AF: 0.00484 AC: 23 AN: 4756

European-Non Finnish (NFE) AF: 0.000273 AC: 253 AN: 925072

Other (OTH) AF: 0.00585 AC: 296 AN: 50594

GnomAD4 genome AF: 0.0234 AC: 3556 AN: 152282 Hom.: 132 Cov.: 32 AF XY: 0.0218 AC XY: 1625 AN XY: 74466

African (AFR) AF: 0.0805 AC: 3346 AN: 41540

American (AMR) AF: 0.00935 AC: 143 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68024

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0194 Hom.: 4

Bravo AF: 0.0276

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.56
PhyloP100		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs112369222; hg19: chr5-141693676;