10-49988750-G-C

Variant names:

• chr10-49988750-G-C
• NM_001077665.3:c.35G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001077665.3(AGAP6):​c.35G>C​(p.Ser12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: AGAP6 NM_001077665.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0650

Genes affected

AGAP6 (HGNC:23466): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 6) Predicted to enable GTPase activator activity and metal ion binding activity. Predicted to be involved in regulation of catalytic activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TIMM23B-AGAP6 (HGNC:45009): (TIMM23B-AGAP6 readthrough (NMD candidate)) This locus represents naturally-occurring readthrough transcription between the adjacent TIMM23B (translocase of inner mitochondrial membrane 23 homolog B) and AGAP6 (ArfGAP with GTPase domain, ankyrin repeat and PH domain 6) genes. Readthrough transcripts contain portions of the coding sequence for both genes and are predicted to be candidates for nonsense-mediated decay (NMD). [provided by RefSeq, Sep 2018]

ENSG00000285803 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058841586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP6	NM_001077665.3	c.35G>C	p.Ser12Thr	missense_variant	Exon 1 of 8	ENST00000412531.7	NP_001071133.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP6	ENST00000412531.7	c.35G>C	p.Ser12Thr	missense_variant	Exon 1 of 8	1	NM_001077665.3	ENSP00000500374.1
TIMM23B-AGAP6	ENST00000651763.1	n.*251-1G>C		splice_acceptor_variant, intron_variant	Intron 9 of 17			ENSP00000502214.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35G>C (p.S12T) alteration is located in exon 1 (coding exon 1) of the AGAP6 gene. This alteration results from a G to C substitution at nucleotide position 35, causing the serine (S) at amino acid position 12 to be replaced by a threonine (T). 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	0.075
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.0
DANN	Benign	0.35
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.13
Sift	Benign	0.093	T;D
Sift4G	Benign	0.40	T;T
Vest4		0.086
MutPred		0.30		Loss of disorder (P = 0.0662);Loss of disorder (P = 0.0662);
MVP		0.055
ClinPred		0.080	T
GERP RS		-2.3
Varity_R		0.054
gMVP		0.030

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-51748510;