NM_173849.3:c.547A>C

Variant names:

• chr14-94769026-T-G
• rs2139703127
• NM_173849.3:c.547A>C

Variant summary

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

The NM_173849.3(GSC):​c.547A>C​(p.Lys183Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GSC NM_173849.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.99
• 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173849.3. 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
	GSC	NM_173849.3	MANE Select	c.547A>C	p.Lys183Gln	missense	Exon 2 of 3	NP_776248.1	P56915

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSC	ENST00000238558.5	TSL:1 MANE Select	c.547A>C	p.Lys183Gln	missense	Exon 2 of 3	ENSP00000238558.3	P56915

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	0.089
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	-0.98	N
PhyloP100		5.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	1.3	N
REVEL	Uncertain	0.54
Sift	Benign	0.086	T
Sift4G	Benign	0.42	T
Polyphen		0.72	P
Vest4		0.75
MutPred		0.50		Loss of methylation at K183 (P = 0.0163)
MVP		0.97
MPC		1.9
ClinPred		0.86	D
GERP RS		5.3
Varity_R		0.33
gMVP		0.78
Mutation Taster		=73/27	polymorphism

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: rs2139703127; hg19: chr14-95235363;