6-138424596-T-G

Variant names:

• chr6-138424596-T-G
• NM_001144060.2:c.4306A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001144060.2(NHSL1):​c.4306A>C​(p.Met1436Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NHSL1 NM_001144060.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41061205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL1	NM_001144060.2	c.4306A>C	p.Met1436Leu	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.4306A>C	p.Met1436Leu	missense_variant	Exon 8 of 8	5	NM_001144060.2	ENSP00000344672.5
NHSL1	ENST00000427025.6	c.4318A>C	p.Met1440Leu	missense_variant	Exon 7 of 7	5		ENSP00000394546.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4318A>C (p.M1440L) alteration is located in exon 7 (coding exon 7) of the NHSL1 gene. This alteration results from a A to C substitution at nucleotide position 4318, causing the methionine (M) at amino acid position 1440 to be replaced by a leucine (L). 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.94	P;.
Vest4		0.62
MutPred		0.34		Loss of MoRF binding (P = 0.0817);.;
MVP		0.19
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.57
gMVP		0.31

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: chr6-138745733;