chr12-85283633-G-A

Variant names:

• chr12-85283633-G-A
• NM_006982.3:c.288G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006982.3(ALX1):​c.288G>A​(p.Met96Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: ALX1 NM_006982.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

Genes affected

ALX1 (HGNC:1494): (ALX homeobox 1) The specific function of this gene has yet to be determined in humans; however, in rodents, it is necessary for survival of the forebrain mesenchyme and may also be involved in development of the cervix. Mutations in the mouse gene lead to neural tube defects such as acrania and meroanencephaly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16507927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALX1	NM_006982.3	c.288G>A	p.Met96Ile	missense_variant	Exon 2 of 4	ENST00000316824.4	NP_008913.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALX1	ENST00000316824.4	c.288G>A	p.Met96Ile	missense_variant	Exon 2 of 4	1	NM_006982.3	ENSP00000315417.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.288G>A (p.M96I) alteration is located in exon 2 (coding exon 2) of the ALX1 gene. This alteration results from a G to A substitution at nucleotide position 288, causing the methionine (M) at amino acid position 96 to be replaced by an isoleucine (I). 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	0.16
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.055
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.19
Sift	Benign	0.11	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.42		Gain of catalytic residue at E91 (P = 0.0214);
MVP		0.70
MPC		0.39
ClinPred		0.87	D
GERP RS		4.5
Varity_R		0.28
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-85677411;