6-138430693-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001144060.2(NHSL1):c.3652G>A(p.Glu1218Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1218Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NHSL1 NM_001144060.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17543977).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHSL1	NM_001144060.2	c.3652G>A	p.Glu1218Lys	missense_variant	6/8	ENST00000343505.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHSL1	ENST00000343505.10	c.3652G>A	p.Glu1218Lys	missense_variant	6/8	5	NM_001144060.2	P3
NHSL1	ENST00000427025.6	c.3664G>A	p.Glu1222Lys	missense_variant	5/7	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2021

The c.3664G>A (p.E1222K) alteration is located in exon 5 (coding exon 5) of the NHSL1 gene. This alteration results from a G to A substitution at nucleotide position 3664, causing the glutamic acid (E) at amino acid position 1222 to be replaced by a lysine (K). 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	0.092
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0068	T;.
Eigen	Benign	0.065
Eigen_PC	Benign	0.0070
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.070
Sift	Benign	0.053	T;D
Sift4G	Benign	0.78	T;T
Polyphen		0.99	D;.
Vest4		0.15
MutPred		0.31		Gain of ubiquitination at E1222 (P = 0.0075);.;
MVP		0.061
ClinPred		0.80	D
GERP RS		3.5
Varity_R		0.10
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-138751830; COSMIC: COSV58676593; COSMIC: COSV58676593;