Variant 6-138424487-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001144060.2(NHSL1):c.4415A>G(p.Asn1472Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 1,551,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 0.000029 ( 0 hom. )

Consequence

NHSL1
NM_001144060.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.666

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035459578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHSL1	NM_001144060.2 linkuse as main transcript	c.4415A>G	p.Asn1472Ser	missense_variant	8/8	ENST00000343505.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHSL1	ENST00000343505.10 linkuse as main transcript	c.4415A>G	p.Asn1472Ser	missense_variant	8/8	5	NM_001144060.2	P3	Q5SYE7-2
NHSL1	ENST00000427025.6 linkuse as main transcript	c.4427A>G	p.Asn1476Ser	missense_variant	7/7	5		A2	Q5SYE7-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000387

AC:

AN:

155032

Hom.:

AF XY:

0.0000365

AC XY:

AN XY:

82246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000459

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000286

AC:

AN:

1399384

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

690198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000616

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000158

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.4427A>G (p.N1476S) alteration is located in exon 7 (coding exon 7) of the NHSL1 gene. This alteration results from a A to G substitution at nucleotide position 4427, causing the asparagine (N) at amino acid position 1476 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.72

Cadd

Benign

7.0

Dann

Benign

0.85

DEOGEN2

Benign

0.0089

T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.67

N;.

MutationTaster

Benign

0.95

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.086

Sift

Benign

0.29

T;T

Sift4G

Benign

0.61

T;T

Polyphen

0.022

B;.

Vest4

0.028

MutPred

0.31

Gain of phosphorylation at N1476 (P = 0.0016);.;

MVP

0.030

ClinPred

0.033

GERP RS

-6.6

Varity_R

0.024

gMVP

0.074

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over