Genetic Variant ARMH4:p.Gln542Glu (chr14-58131719-G-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001001872.4(ARMH4):c.1624C>G(p.Gln542Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00833 in 1,612,316 control chromosomes in the GnomAD database, including 107 homozygotes. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.0078 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0084 ( 97 hom. )

Consequence

ARMH4
NM_001001872.4 missense, splice_region

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.396

Publications

6 publications found

Variant links:

Genes affected

ARMH4 (HGNC:19846): (armadillo like helical domain containing 4) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARMH4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 14-58131719-G-C is Benign according to our data. Variant chr14-58131719-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2644257.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00839 (12246/1460004) while in subpopulation MID AF = 0.0212 (98/4616). AF 95% confidence interval is 0.0178. There are 97 homozygotes in GnomAdExome4. There are 5922 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001872.4. 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
	ARMH4	NM_001001872.4	MANE Select	c.1624C>G	p.Gln542Glu	missense splice_region	Exon 4 of 8	NP_001001872.2	Q86TY3-1
	ARMH4	NM_001320173.3		c.1624C>G	p.Gln542Glu	missense splice_region	Exon 4 of 5	NP_001307102.1	Q86TY3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARMH4	ENST00000267485.7	TSL:1 MANE Select	c.1624C>G	p.Gln542Glu	missense splice_region	Exon 4 of 8	ENSP00000267485.7	Q86TY3-1
ARMH4	ENST00000334342.5	TSL:1	n.1789C>G		splice_region non_coding_transcript_exon	Exon 4 of 5
ARMH4	ENST00000912025.1		c.1624C>G	p.Gln542Glu	missense splice_region	Exon 4 of 8	ENSP00000582084.1

Frequencies

GnomAD3 genomes

AF:

0.00783

AC:

1191

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0435

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00807

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00851

AC:

2135

AN:

251026

AF XY:

0.00817

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0427

Gnomad NFE exome

AF:

0.00866

Gnomad OTH exome

AF:

0.00980

GnomAD4 exome

AF:

0.00839

AC:

12246

AN:

1460004

Hom.:

Cov.:

AF XY:

0.00815

AC XY:

5922

AN XY:

726328

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

33416

American (AMR)

AF:

0.00248

AC:

111

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00192

AC:

165

AN:

86156

European-Finnish (FIN)

AF:

0.0406

AC:

2165

AN:

53334

Middle Eastern (MID)

AF:

0.0212

AC:

AN:

4616

European-Non Finnish (NFE)

AF:

0.00826

AC:

9178

AN:

1111694

Other (OTH)

AF:

0.00712

AC:

429

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

524

1048

1573

2097

2621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00782

AC:

1191

AN:

152312

Hom.:

Cov.:

AF XY:

0.00920

AC XY:

685

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41568

American (AMR)

AF:

0.00490

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0435

AC:

462

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00807

AC:

549

AN:

68018

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00691

Hom.:

Bravo

AF:

0.00502

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00849

AC:

ExAC

AF:

0.00779

AC:

946

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00741

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

3.4

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0012

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.98

PhyloP100

-0.40

PROVEAN

Benign

-0.33

REVEL

Benign

0.032

Sift

Benign

0.35

Sift4G

Benign

0.98

Polyphen

0.015

Vest4

0.30

MVP

0.030

MPC

0.044

ClinPred

0.0024

GERP RS

-2.4

Varity_R

0.040

gMVP

0.091

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.46

Position offset: -1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over