chr1-119798503-T-G

Position:

• chr1-119798503-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032044.4(REG4):​c.403A>C​(p.Asn135His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,613,034 control chromosomes in the GnomAD database, including 345 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N135S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (183 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (162 hom.)
• Consequence: REG4 NM_032044.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0130

Genes affected

REG4 (HGNC:22977): (regenerating family member 4) Enables heparin binding activity and mannan binding activity. Predicted to act upstream of or within response to bacterium. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019979477).
• BP6: Variant 1-119798503-T-G is Benign according to our data. Variant chr1-119798503-T-G is described in ClinVar as [Benign]. Clinvar id is 775138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REG4	NM_032044.4	c.403A>C	p.Asn135His	missense_variant	5/6	ENST00000256585.10	NP_114433.1
REG4	NM_001159352.2	c.403A>C	p.Asn135His	missense_variant	6/7		NP_001152824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REG4	ENST00000256585.10	c.403A>C	p.Asn135His	missense_variant	5/6	1	NM_032044.4	ENSP00000256585.5
REG4	ENST00000354219.5	c.403A>C	p.Asn135His	missense_variant	6/7	1		ENSP00000346158.1
REG4	ENST00000530654.1	c.303+1222A>C		intron_variant		5		ENSP00000437135.1

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3866 AN: 152182 Hom.: 181 Cov.: 32

Gnomad AFR AF: 0.0884

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00679 AC: 1706 AN: 251378 Hom.: 81 AF XY: 0.00492 AC XY: 669 AN XY: 135856

Gnomad AFR exome AF: 0.0918

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00268 AC: 3916 AN: 1460734 Hom.: 162 Cov.: 30 AF XY: 0.00227 AC XY: 1652 AN XY: 726768

Gnomad4 AFR exome AF: 0.0902

Gnomad4 AMR exome AF: 0.00512

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000213

Gnomad4 OTH exome AF: 0.00613

GnomAD4 genome AF: 0.0255 AC: 3880 AN: 152300 Hom.: 183 Cov.: 32 AF XY: 0.0249 AC XY: 1853 AN XY: 74488

Gnomad4 AFR AF: 0.0885

Gnomad4 AMR AF: 0.00909

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00513 Hom.: 39

Bravo AF: 0.0296

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0876 AC: 386

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00857 AC: 1041

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0034	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.30	.;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.29	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.0020
Sift	Benign	0.21	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0	B;B
Vest4		0.16
MVP		0.092
MPC		0.097
ClinPred		0.0028	T
GERP RS		-1.1
Varity_R		0.064
gMVP		0.076

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34996202; hg19: chr1-120341126;