6-138424298-G-C

Variant names:

• chr6-138424298-G-C
• rs991180311
• NM_001144060.2:c.4604C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001144060.2(NHSL1):​c.4604C>G​(p.Pro1535Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,360,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P1535L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: NHSL1 NM_001144060.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16773409).

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.4604C>G	p.Pro1535Arg	missense	Exon 8 of 8	NP_001137532.1	Q5SYE7-2
	NHSL1	NM_020464.2		c.4616C>G	p.Pro1539Arg	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.4604C>G	p.Pro1535Arg	missense	Exon 8 of 8	ENSP00000344672.5	Q5SYE7-2
	NHSL1	ENST00000491526.7	TSL:3	c.4835C>G	p.Pro1612Arg	missense	Exon 8 of 8	ENSP00000433523.2	H0YDF6
	NHSL1	ENST00000427025.6	TSL:5	c.4616C>G	p.Pro1539Arg	missense	Exon 7 of 7	ENSP00000394546.2	Q5SYE7-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000441 AC: 6 AN: 1360958 Hom.: 0 Cov.: 33 AF XY: 0.00000300 AC XY: 2 AN XY: 666854

African (AFR) AF: 0.00 AC: 0 AN: 30514

American (AMR) AF: 0.00 AC: 0 AN: 31530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22386

East Asian (EAS) AF: 0.000170 AC: 6 AN: 35330

South Asian (SAS) AF: 0.00 AC: 0 AN: 73664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1058898

Other (OTH) AF: 0.00 AC: 0 AN: 56180

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.23	T
Polyphen		0.59	P
Vest4		0.13
MutPred		0.15		Gain of helix (P = 0.0078)
MVP		0.20
ClinPred		0.88	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.13
Mutation Taster		=89/11	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: rs991180311; hg19: chr6-138745435;