14-94769660-C-T

Variant names:

• chr14-94769660-C-T
• rs587777290
• NM_173849.3:c.355+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_173849.3(GSC):​c.355+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000156 in 1,283,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: GSC NM_173849.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.54
• Publications: 0 publications found

Genes affected

GSC (HGNC:4612): (goosecoid homeobox) This gene encodes a member of the bicoid subfamily of the paired (PRD) homeobox family of proteins. The encoded protein acts as a transcription factor and may be autoregulatory. A similar protein in mice plays a role in craniofacial and rib cage development during embryogenesis. [provided by RefSeq, Jul 2008]

GSC Gene-Disease associations (from GenCC):

• short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.5852713 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSC	NM_173849.3	c.355+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	ENST00000238558.5	NP_776248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSC	ENST00000238558.5	c.355+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	1	NM_173849.3	ENSP00000238558.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1283452 Hom.: 0 Cov.: 32 AF XY: 0.00000159 AC XY: 1 AN XY: 629722

African (AFR) AF: 0.00 AC: 0 AN: 25244

American (AMR) AF: 0.00 AC: 0 AN: 18902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20320

East Asian (EAS) AF: 0.00 AC: 0 AN: 30026

South Asian (SAS) AF: 0.00 AC: 0 AN: 63276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3720

European-Non Finnish (NFE) AF: 0.00000193 AC: 2 AN: 1037102

Other (OTH) AF: 0.00 AC: 0 AN: 53092

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		4.5
GERP RS		3.5
PromoterAI		-0.15	Neutral
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs587777290; hg19: chr14-95235997;