X-155670185-A-G

Variant names:

• chrX-155670185-A-G
• rs473491
• NM_001304990.2:c.-282+57538A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001304990.2(SPRY3):​c.-282+57538A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 110,429 control chromosomes in the GnomAD database, including 14,230 homozygotes. There are 18,124 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (14230 hom., 18124 hem., cov: 22)
• Consequence: SPRY3 NM_001304990.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.253
• Publications: 3 publications found

Genes affected

SPRY3 (HGNC:11271): (sprouty RTK signaling antagonist 3) Involved in negative regulation of MAPK cascade. Predicted to be located in membrane. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TMLHE (HGNC:18308): (trimethyllysine hydroxylase, epsilon) This gene encodes the protein trimethyllysine dioxygenase which is the first enzyme in the carnitine biosynthesis pathway. Carnitine play an essential role in the transport of activated fatty acids across the inner mitochondrial membrane. The encoded protein converts trimethyllysine into hydroxytrimethyllysine. A pseudogene of this gene is found on chromosome X. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

TMLHE Gene-Disease associations (from GenCC):

• epsilon-trimethyllysine hydroxylase deficiency

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• autism spectrum disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRY3	NM_001304990.2	c.-282+57538A>G		intron_variant	Intron 1 of 2	ENST00000695325.1	NP_001291919.1
SPRY3	NM_001394353.1	c.-282+13160A>G		intron_variant	Intron 2 of 3		NP_001381282.1
SPRY3	NM_001394354.1	c.-350+57538A>G		intron_variant	Intron 1 of 3		NP_001381283.1
SPRY3	NM_001394355.1	c.-719+57538A>G		intron_variant	Intron 1 of 3		NP_001381284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRY3	ENST00000695325.1	c.-282+57538A>G		intron_variant	Intron 1 of 2		NM_001304990.2	ENSP00000511806.1
TMLHE	ENST00000675642.1	c.-152-244T>C		intron_variant	Intron 1 of 8			ENSP00000502604.1
SPRY3	ENST00000675360.1	c.-282+13160A>G		intron_variant	Intron 2 of 3			ENSP00000502489.1
SPRY3	ENST00000676089.1	n.76+57538A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.547 AC: 60405 AN: 110377 Hom.: 14234 Cov.: 22

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.749

Gnomad MID AF: 0.764

Gnomad NFE AF: 0.723

Gnomad OTH AF: 0.577

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.547 AC: 60399 AN: 110429 Hom.: 14230 Cov.: 22 AF XY: 0.552 AC XY: 18124 AN XY: 32843

African (AFR) AF: 0.134 AC: 4119 AN: 30724

American (AMR) AF: 0.613 AC: 6324 AN: 10317

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 1932 AN: 2617

East Asian (EAS) AF: 0.722 AC: 2508 AN: 3476

South Asian (SAS) AF: 0.677 AC: 1785 AN: 2638

European-Finnish (FIN) AF: 0.749 AC: 4365 AN: 5825

Middle Eastern (MID) AF: 0.769 AC: 166 AN: 216

European-Non Finnish (NFE) AF: 0.723 AC: 37893 AN: 52437

Other (OTH) AF: 0.571 AC: 856 AN: 1500

Alfa AF: 0.641 Hom.: 26684

Bravo AF: 0.524

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.5
DANN	Benign	0.78
PhyloP100		0.25

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs473491; hg19: chrX-154899846;