17-42190677-T-C

Variant names:

• chr17-42190677-T-C
• rs1401251916
• NM_032484.5:c.1235A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032484.5(GHDC):​c.1235A>G​(p.Gln412Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GHDC NM_032484.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

Genes affected

GHDC (HGNC:24438): (GH3 domain containing) Predicted to enable acid-amino acid ligase activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3774966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHDC	NM_032484.5	c.1235A>G	p.Gln412Arg	missense_variant	Exon 8 of 10	ENST00000587427.6	NP_115873.1
GHDC	NM_001142623.2	c.1235A>G	p.Gln412Arg	missense_variant	Exon 8 of 10		NP_001136095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHDC	ENST00000587427.6	c.1235A>G	p.Gln412Arg	missense_variant	Exon 8 of 10	1	NM_032484.5	ENSP00000467585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461528 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000469 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1235A>G (p.Q412R) alteration is located in exon 8 (coding exon 6) of the GHDC gene. This alteration results from a A to G substitution at nucleotide position 1235, causing the glutamine (Q) at amino acid position 412 to be replaced by an arginine (R). 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	Benign	0.091
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	.;T;.;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.62	T;.;.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	.;M;M;M;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	.;N;N;.;.
REVEL	Benign	0.16
Sift	Benign	0.19	.;T;T;.;.
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.99, 0.99	.;D;D;D;D
Vest4		0.46
MutPred		0.55		Gain of methylation at Q412 (P = 0.0321);Gain of methylation at Q412 (P = 0.0321);Gain of methylation at Q412 (P = 0.0321);Gain of methylation at Q412 (P = 0.0321);Gain of methylation at Q412 (P = 0.0321);
MVP		0.26
MPC		0.39
ClinPred		0.80	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1401251916; hg19: chr17-40342695;