6-138430396-C-T

Variant names:

• chr6-138430396-C-T
• rs749650141
• NM_001144060.2:c.3949G>A

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.3949G>A​(p.Ala1317Thr) 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. 16/22 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. A1317S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NHSL1 NM_001144060.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.100
• 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=0.048942894).

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.3949G>A	p.Ala1317Thr	missense	Exon 6 of 8	NP_001137532.1	Q5SYE7-2
	NHSL1	NM_020464.2		c.3961G>A	p.Ala1321Thr	missense	Exon 5 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.3949G>A	p.Ala1317Thr	missense	Exon 6 of 8	ENSP00000344672.5	Q5SYE7-2
	NHSL1	ENST00000491526.7	TSL:3	c.4180G>A	p.Ala1394Thr	missense	Exon 6 of 8	ENSP00000433523.2	H0YDF6
	NHSL1	ENST00000427025.6	TSL:5	c.3961G>A	p.Ala1321Thr	missense	Exon 5 of 7	ENSP00000394546.2	Q5SYE7-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 101556 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1321154 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 641364

African (AFR) AF: 0.00 AC: 0 AN: 29428

American (AMR) AF: 0.00 AC: 0 AN: 25956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20100

East Asian (EAS) AF: 0.00 AC: 0 AN: 34902

South Asian (SAS) AF: 0.00 AC: 0 AN: 65690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1038558

Other (OTH) AF: 0.00 AC: 0 AN: 54668

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000556 Hom.: 1

ExAC AF: 0.0000730 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.10
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.019
Sift	Benign	0.63	T
Sift4G	Benign	0.57	T
Polyphen		0.26	B
Vest4		0.053
MutPred		0.27		Gain of glycosylation at A1321 (P = 0.0128)
MVP		0.014
ClinPred		0.17	T
GERP RS		0.92
Varity_R		0.11
gMVP		0.049
Mutation Taster		=97/3	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: rs749650141; hg19: chr6-138751533; COSMIC: COSV105209957; COSMIC: COSV105209957;