6-138424169-T-A

Variant names:

• chr6-138424169-T-A
• rs903351736
• NM_001144060.2:c.4733A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001144060.2(NHSL1):​c.4733A>T​(p.Gln1578Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000765 in 1,307,814 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. 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. Q1578R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: NHSL1 NM_001144060.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050697982).

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>T	p.Gln1578Leu	missense	Exon 8 of 8	NP_001137532.1	Q5SYE7-2
	NHSL1	NM_020464.2		c.4745A>T	p.Gln1582Leu	missense	Exon 7 of 7	NP_065197.1	Q5SYE7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHSL1	ENST00000343505.10	TSL:5 MANE Select	c.4733A>T	p.Gln1578Leu	missense	Exon 8 of 8	ENSP00000344672.5	Q5SYE7-2
	NHSL1	ENST00000491526.7	TSL:3	c.4964A>T	p.Gln1655Leu	missense	Exon 8 of 8	ENSP00000433523.2	H0YDF6
	NHSL1	ENST00000427025.6	TSL:5	c.4745A>T	p.Gln1582Leu	missense	Exon 7 of 7	ENSP00000394546.2	Q5SYE7-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.65e-7 AC: 1 AN: 1307814 Hom.: 0 Cov.: 32 AF XY: 0.00000157 AC XY: 1 AN XY: 637682

African (AFR) AF: 0.00 AC: 0 AN: 28788

American (AMR) AF: 0.00 AC: 0 AN: 22172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19688

East Asian (EAS) AF: 0.00 AC: 0 AN: 35048

South Asian (SAS) AF: 0.00 AC: 0 AN: 66260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5300

European-Non Finnish (NFE) AF: 9.60e-7 AC: 1 AN: 1042062

Other (OTH) AF: 0.00 AC: 0 AN: 54310

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.2
DANN	Benign	0.66
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.042
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.047
Sift	Benign	0.039	D
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.071
MutPred		0.10		Loss of solvent accessibility (P = 0.0056)
MVP		0.030
ClinPred		0.053	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.087
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs903351736; hg19: chr6-138745306;