1-220884304-C-T

Variant names:

• chr1-220884304-C-T
• rs2738755
• NM_021958.4:c.1067C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021958.4(HLX):​c.1067C>T​(p.Pro356Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,612,712 control chromosomes in the GnomAD database, including 90,502 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (10122 hom., cov: 31)
  • Exomes 𝑓: 0.33 (80380 hom.)
• Consequence: HLX NM_021958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.613
• Publications: 34 publications found

Genes affected

HLX (HGNC:4978): (H2.0 like homeobox) Enables sequence-specific DNA binding activity. Predicted to be involved in cell differentiation and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including animal organ development; enteric nervous system development; and regulation of T-helper cell differentiation. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000286231 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010964274).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLX	NM_021958.4	c.1067C>T	p.Pro356Leu	missense_variant	Exon 4 of 4	ENST00000366903.8	NP_068777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLX	ENST00000366903.8	c.1067C>T	p.Pro356Leu	missense_variant	Exon 4 of 4	1	NM_021958.4	ENSP00000355870.5
ENSG00000286231	ENST00000651706.1	n.*375C>T		non_coding_transcript_exon_variant	Exon 9 of 9			ENSP00000499157.1
ENSG00000286231	ENST00000651706.1	n.*375C>T		3_prime_UTR_variant	Exon 9 of 9			ENSP00000499157.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54189 AN: 151600 Hom.: 10108 Cov.: 31

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.0910

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.372

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.345

GnomAD2 exomes AF: 0.312 AC: 77785 AN: 249472 AF XY: 0.311

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.272

Gnomad ASJ exome AF: 0.450

Gnomad EAS exome AF: 0.0575

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.327 AC: 477595 AN: 1460992 Hom.: 80380 Cov.: 39 AF XY: 0.325 AC XY: 236385 AN XY: 726712

African (AFR) AF: 0.447 AC: 14961 AN: 33474

American (AMR) AF: 0.279 AC: 12468 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 11677 AN: 26100

East Asian (EAS) AF: 0.106 AC: 4209 AN: 39694

South Asian (SAS) AF: 0.257 AC: 22181 AN: 86226

European-Finnish (FIN) AF: 0.355 AC: 18914 AN: 53312

Middle Eastern (MID) AF: 0.432 AC: 2493 AN: 5766

European-Non Finnish (NFE) AF: 0.333 AC: 370496 AN: 1111410

Other (OTH) AF: 0.335 AC: 20196 AN: 60360

GnomAD4 genome AF: 0.357 AC: 54237 AN: 151720 Hom.: 10122 Cov.: 31 AF XY: 0.352 AC XY: 26107 AN XY: 74136

African (AFR) AF: 0.446 AC: 18441 AN: 41342

American (AMR) AF: 0.309 AC: 4714 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1582 AN: 3470

East Asian (EAS) AF: 0.0905 AC: 465 AN: 5140

South Asian (SAS) AF: 0.245 AC: 1177 AN: 4808

European-Finnish (FIN) AF: 0.366 AC: 3835 AN: 10488

Middle Eastern (MID) AF: 0.376 AC: 109 AN: 290

European-Non Finnish (NFE) AF: 0.337 AC: 22870 AN: 67906

Other (OTH) AF: 0.342 AC: 721 AN: 2106

Alfa AF: 0.341 Hom.: 29552

Bravo AF: 0.358

TwinsUK AF: 0.334 AC: 1239

ALSPAC AF: 0.325 AC: 1251

ESP6500AA AF: 0.428 AC: 1884

ESP6500EA AF: 0.351 AC: 3017

ExAC AF: 0.315 AC: 38176

Asia WGS AF: 0.201 AC: 702 AN: 3478

EpiCase AF: 0.351

EpiControl AF: 0.353

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0011	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		0.61
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.020
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.36	T;T
Vest4		0.041
ClinPred		0.0064	T
GERP RS		2.0
Varity_R		0.044
gMVP		0.38
Mutation Taster		=95/5	polymorphism (auto)

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: rs2738755; hg19: chr1-221057646; COSMIC: COSV65044543; COSMIC: COSV65044543;