chr3-158105989-A-C

Variant names:

• chr3-158105989-A-C
• rs1014140147
• NM_001163678.2:c.36T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001163678.2(SHOX2):​c.36T>G​(p.Phe12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SHOX2 NM_001163678.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82
• Publications: 0 publications found

Genes affected

SHOX2 (HGNC:10854): (SHOX homeobox 2) This gene is a member of the homeobox family of genes that encode proteins containing a 60-amino acid residue motif that represents a DNA binding domain. Homeobox genes have been characterized extensively as transcriptional regulators involved in pattern formation in both invertebrate and vertebrate species. Several human genetic disorders are caused by aberrations in human homeobox genes. This locus represents a pseudoautosomal homeobox gene that is thought to be responsible for idiopathic short stature, and it is implicated in the short stature phenotype of Turner syndrome patients. This gene is considered to be a candidate gene for Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

RSRC1 (HGNC:24152): (arginine and serine rich coiled-coil 1) This gene encodes a member of the serine and arginine rich-related protein family. The encoded protein is involved in both constitutive and alternative mRNA splicing. This gene may be associated with schizophrenia. A pseudogene of this gene is located on chromosome 9. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2012]

RSRC1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 70

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX2	NM_001163678.2	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 5	ENST00000483851.7	NP_001157150.1
SHOX2	NM_003030.4	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 6		NP_003021.3
SHOX2	NM_006884.3	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 5		NP_006875.2
SHOX2	XM_006713727.4	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 6		XP_006713790.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX2	ENST00000483851.7	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 5	2	NM_001163678.2	ENSP00000419362.1
SHOX2	ENST00000389589.8	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 6	1		ENSP00000374240.4
SHOX2	ENST00000441443.6	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 5	5		ENSP00000397099.3
RSRC1	ENST00000480820.5	c.-24A>C		5_prime_UTR_variant	Exon 1 of 10	5		ENSP00000420150.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245238 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460860 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726704

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111752

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.36T>G (p.F12L) alteration is located in exon 1 (coding exon 1) of the SHOX2 gene. This alteration results from a T to G substitution at nucleotide position 36, causing the phenylalanine (F) at amino acid position 12 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.5	L;L;L
PhyloP100		1.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.5	.;N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.034	.;D;D
Sift4G	Uncertain	0.053	T;D;T
Polyphen		0.53	P;D;B
Vest4		0.58
MutPred		0.36		Gain of glycosylation at S11 (P = 0.012);Gain of glycosylation at S11 (P = 0.012);Gain of glycosylation at S11 (P = 0.012);
MVP		0.94
MPC		1.6
ClinPred		0.94	D
GERP RS		1.4
PromoterAI		-0.035	Neutral
Varity_R		0.27
gMVP		0.58
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1014140147; hg19: chr3-157823778;