Genetic Variant NHSL1:p.Gln1578Arg (chr6-138424169-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001144060.2(NHSL1):c.4733A>G(p.Gln1578Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,459,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

NHSL1
NM_001144060.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0420

Publications

0 publications found

Variant links:

Genes affected

NHSL1 (HGNC:21021): (NHS like 1) Predicted to be involved in cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

NHSL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04103288).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144060.2. 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
	NHSL1	NM_001144060.2	MANE Select	c.4733A>G	p.Gln1578Arg	missense	Exon 8 of 8	NP_001137532.1	Q5SYE7-2
	NHSL1	NM_020464.2		c.4745A>G	p.Gln1582Arg	missense	Exon 7 of 7	NP_065197.1	Q5SYE7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NHSL1	ENST00000343505.10	TSL:5 MANE Select	c.4733A>G	p.Gln1578Arg	missense	Exon 8 of 8	ENSP00000344672.5	Q5SYE7-2
NHSL1	ENST00000491526.7	TSL:3	c.4964A>G	p.Gln1655Arg	missense	Exon 8 of 8	ENSP00000433523.2	H0YDF6
NHSL1	ENST00000427025.6	TSL:5	c.4745A>G	p.Gln1582Arg	missense	Exon 7 of 7	ENSP00000394546.2	Q5SYE7-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

79576

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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:

0.0000153

AC:

AN:

1307814

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

637682

show subpopulations

African (AFR)

AF:

0.000486

AC:

AN:

28788

American (AMR)

AF:

0.00

AC:

AN:

22172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19688

East Asian (EAS)

AF:

0.00

AC:

AN:

35048

South Asian (SAS)

AF:

0.00

AC:

AN:

66260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5300

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1042062

Other (OTH)

AF:

0.000110

AC:

AN:

54310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.4

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.0047

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.53

M_CAP

Benign

0.0046

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

-0.042

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.50

REVEL

Benign

0.048

Sift

Benign

0.44

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.022

MutPred

0.060

Gain of methylation at Q1582 (P = 0.0717)

MVP

0.014

ClinPred

0.022

GERP RS

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.022

gMVP

0.038

Mutation Taster

=100/0

polymorphism

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over