NM_001177479.2:c.1120A>G

Variant names:

• chrX-84468603-T-C
• rs141686783
• NM_001177479.2:c.1120A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001177479.2(HDX):​c.1120A>G​(p.Thr374Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,204,975 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.0000092 (0 hom. 2 hem.)
• Consequence: HDX NM_001177479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• Publications: 1 publications found

Genes affected

HDX (HGNC:26411): (highly divergent homeobox) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039604843).
• BS2: High Hemizygotes in GnomAd4 at 8 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177479.2. 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
	HDX	NM_001177479.2	MANE Select	c.1120A>G	p.Thr374Ala	missense	Exon 4 of 11	NP_001170950.1	Q7Z353-1
	HDX	NM_144657.5		c.1120A>G	p.Thr374Ala	missense	Exon 3 of 10	NP_653258.2
	HDX	NM_001177478.2		c.946A>G	p.Thr316Ala	missense	Exon 3 of 10	NP_001170949.1	Q7Z353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDX	ENST00000373177.3	TSL:1 MANE Select	c.1120A>G	p.Thr374Ala	missense	Exon 4 of 11	ENSP00000362272.2	Q7Z353-1
	HDX	ENST00000297977.9	TSL:1	c.1120A>G	p.Thr374Ala	missense	Exon 3 of 10	ENSP00000297977.5	Q7Z353-1
	HDX	ENST00000851225.1		c.1120A>G	p.Thr374Ala	missense	Exon 4 of 11	ENSP00000521284.1

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 17 AN: 112105 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000654

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183336 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000915 AC: 10 AN: 1092817 Hom.: 0 Cov.: 29 AF XY: 0.00000558 AC XY: 2 AN XY: 358431

African (AFR) AF: 0.000267 AC: 7 AN: 26263

American (AMR) AF: 0.0000284 AC: 1 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19350

East Asian (EAS) AF: 0.00 AC: 0 AN: 30174

South Asian (SAS) AF: 0.00 AC: 0 AN: 54008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4125

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837264

Other (OTH) AF: 0.0000218 AC: 1 AN: 45908

GnomAD4 genome AF: 0.000152 AC: 17 AN: 112158 Hom.: 0 Cov.: 23 AF XY: 0.000233 AC XY: 8 AN XY: 34314

African (AFR) AF: 0.000421 AC: 13 AN: 30896

American (AMR) AF: 0.000283 AC: 3 AN: 10607

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2697

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6107

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53199

Other (OTH) AF: 0.000646 AC: 1 AN: 1547

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.95
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.044	T
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.079
Sift	Benign	0.25	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.13
MPC		0.12
ClinPred		0.029	T
GERP RS		2.8
Varity_R		0.035
gMVP		0.25
Mutation Taster		=99/1	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: rs141686783; hg19: chrX-83723611;