5-135535648-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006161.3(NEUROG1):c.43G>T(p.Ala15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,583,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A15V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: NEUROG1 NM_006161.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.19

Genes affected

NEUROG1 (HGNC:7764): (neurogenin 1) Enables E-box binding activity and protein homodimerization activity. Involved in several processes, including animal organ morphogenesis; cranial nerve development; and hard palate morphogenesis. Predicted to be located in neuronal cell body. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

SLC25A48 (HGNC:30451): (solute carrier family 25 member 48) Predicted to enable acyl carnitine transmembrane transporter activity. Predicted to be involved in acyl carnitine transport and amino acid transport. Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052814007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEUROG1	NM_006161.3	c.43G>T	p.Ala15Ser	missense_variant	1/1	ENST00000314744.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEUROG1	ENST00000314744.6	c.43G>T	p.Ala15Ser	missense_variant	1/1		NM_006161.3	P1
	ENST00000698884.1	n.496+48879C>A		intron_variant, non_coding_transcript_variant
SLC25A48	ENST00000698885.1	n.364+25892C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 23 AN: 214728 Hom.: 0 AF XY: 0.000101 AC XY: 12 AN XY: 118770

Gnomad AFR exome AF: 0.000162

Gnomad AMR exome AF: 0.000102

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: 0.000170

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.000198 AC: 284 AN: 1431038 Hom.: 0 Cov.: 31 AF XY: 0.000183 AC XY: 130 AN XY: 711362

Gnomad4 AFR exome AF: 0.000228

Gnomad4 AMR exome AF: 0.0000757

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.000220

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74392

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000225 Hom.: 2

Bravo AF: 0.000117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000373 AC: 3

ExAC AF: 0.0000924 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.43G>T (p.A15S) alteration is located in exon 1 (coding exon 1) of the NEUROG1 gene. This alteration results from a G to T substitution at nucleotide position 43, causing the alanine (A) at amino acid position 15 to be replaced by a serine (S). 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	Benign	0.072
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	5.1
Dann	Benign	0.91
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.21
Sift	Benign	0.18	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.077
MVP		0.43
MPC		0.45
ClinPred		0.0078	T
GERP RS		-0.55
Varity_R		0.081
gMVP		0.13

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: rs143170722; hg19: chr5-134871338;