6-138424548-A-G

Variant names:

• chr6-138424548-A-G
• rs1401758623
• NM_001144060.2:c.4354T>C

Variant summary

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

The NM_001144060.2(NHSL1):​c.4354T>C​(p.Ser1452Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1452T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NHSL1 NM_001144060.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.523

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=0.095810175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL1	NM_001144060.2	c.4354T>C	p.Ser1452Pro	missense_variant	Exon 8 of 8	ENST00000343505.10	NP_001137532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHSL1	ENST00000343505.10	c.4354T>C	p.Ser1452Pro	missense_variant	Exon 8 of 8	5	NM_001144060.2	ENSP00000344672.5
NHSL1	ENST00000427025.6	c.4366T>C	p.Ser1456Pro	missense_variant	Exon 7 of 7	5		ENSP00000394546.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000640 AC: 1 AN: 156218 Hom.: 0 AF XY: 0.0000121 AC XY: 1 AN XY: 82822

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 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 Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0087	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.040
Sift	Benign	0.20	T;T
Sift4G	Benign	0.073	T;T
Polyphen		0.69	P;.
Vest4		0.091
MutPred		0.25		Loss of phosphorylation at S1456 (P = 0.002);.;
MVP		0.081
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.23
gMVP		0.30

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

Other links and lift over

dbSNP: rs1401758623; hg19: chr6-138745685;