12-85280452-G-T

Variant names:

• chr12-85280452-G-T
• rs115596276
• NM_006982.3:c.191G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006982.3(ALX1):​c.191G>T​(p.Arg64Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00617 in 1,611,802 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R64C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (39 hom.)
• Consequence: ALX1 NM_006982.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.82
• Publications: 12 publications found

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]

ALX1 Gene-Disease associations (from GenCC):

• frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01105988).
• BP6: Variant 12-85280452-G-T is Benign according to our data. Variant chr12-85280452-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 287469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 39 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006982.3. 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
	ALX1	NM_006982.3	MANE Select	c.191G>T	p.Arg64Leu	missense	Exon 1 of 4	NP_008913.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALX1	ENST00000316824.4	TSL:1 MANE Select	c.191G>T	p.Arg64Leu	missense	Exon 1 of 4	ENSP00000315417.3

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 626 AN: 152056 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00670

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00432 AC: 1076 AN: 249354 AF XY: 0.00444

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.00316

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.00696

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00638 AC: 9316 AN: 1459628 Hom.: 39 Cov.: 32 AF XY: 0.00619 AC XY: 4497 AN XY: 726108

African (AFR) AF: 0.00111 AC: 37 AN: 33426

American (AMR) AF: 0.00306 AC: 137 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00273 AC: 235 AN: 86186

European-Finnish (FIN) AF: 0.00229 AC: 121 AN: 52728

Middle Eastern (MID) AF: 0.00714 AC: 32 AN: 4480

European-Non Finnish (NFE) AF: 0.00756 AC: 8402 AN: 1111990

Other (OTH) AF: 0.00508 AC: 306 AN: 60262

GnomAD4 genome AF: 0.00410 AC: 624 AN: 152174 Hom.: 1 Cov.: 32 AF XY: 0.00397 AC XY: 295 AN XY: 74390

African (AFR) AF: 0.00120 AC: 50 AN: 41510

American (AMR) AF: 0.00445 AC: 68 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4818

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10592

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00669 AC: 455 AN: 68012

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00571 Hom.: 9

Bravo AF: 0.00440

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00428 AC: 520

EpiCase AF: 0.00692

EpiControl AF: 0.00723

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome (2)
-	-	1	ALX1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.080	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.2	L
PhyloP100		3.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.020	D
Sift4G	Benign	0.65	T
Polyphen		0.96	D
Vest4		0.63
MVP		0.97
MPC		0.45
ClinPred		0.035	T
GERP RS		5.5
PromoterAI		0.066	Neutral
Varity_R		0.29
gMVP		0.44
Mutation Taster		=93/7	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: rs115596276; hg19: chr12-85674230; COSMIC: COSV108150649;